Formulation Development and Design of Discriminatory Dissolution Medium for Controlled Release Amorphous Solid Dispersion of Apremilast for Once A Day Administration: A QbD Approach

Formulation Development and Design of Discriminatory Dissolution Medium for Controlled Release Amorphous Solid Dispersion of Apremilast for Once A Day Administration: A QbD Approach | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Formulation Development and Design of Discriminatory Dissolution Medium for Controlled Release Amorphous Solid Dispersion of Apremilast for Once A Day Administration: A QbD Approach Sandipan Roy, Apoorva Phadke, Nehal Sarvaiya, Vaishali Londhe, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8916904/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose The study was aimed to formulate a novel once a day Controlled Release Amorphous Solid Dispersion (CASD) and design a discriminatory dissolution method for analysis of the release behaviour. Methods Apremilast and Kollidon® VA 64 (1:2) were formulated into an amorphous solid dispersion by QbD enabled hot melt extrusion (HME). The extrudates were mixed with high-viscosity Hypromellose, colloidal silicon dioxide as glidant, and stearic acid as lubricant to form tablets. Initial dissolution parameters were determined using the One Factor at A Time (OFAT) method, later refined through Design of Experiment (DoE) approach with three variables—agitation speed, media volume, and surfactant concentration that validate the dissolution method, resulting in a curated design space based on the defined specifications. The discriminatory capacity of the finalized dissolution media was evaluated by altering critical quality attributes (CQAs) like polymer concentration and critical process parameters (CPP) like tablet hardness. Results Dissolution parameters such as pH (4.5), surfactant concentration (1%w/w Tween® 80), volume (900mL), agitation speed (75rpm), and apparatus (type II) were found to significantly influence method development, enabling the detection of minor variations in formulation attributes and manufacturing process parameters. Conclusion This QbD-DoE based study of formulation development and design of discriminatory dissolution of Apremilast CASD offers a novel once a day substitute to the traditional high dose multi-frequency regime with an effective discriminatory dissolution medium ensuring reliable product performance against subtle formulation differences. showcases successful application of QbD based development approach. The selected dissolution method effectively discriminates against subtle formulation differences, ensuring reliable product performance. Graphical Abstract Controlled Amorphous Release Solid Dispersion (CASD) Quality by Design (QbD) Once A Day Dosing Dissolution Development Design of Experiment (DoE) Discriminatory Dissolution Medium Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction In pharmaceutical development, adopting a QbD approach allows thorough understanding of the formulation and manufacturing process [ 1 – 3 ]. For Controlled Release (CR) formulations based on Amorphous Solid Dispersions (ASDs), this framework becomes especially essential due to the process as well as material variables, their interplay and its impact on stability and performance of the delivery system [ 4 – 6 ]. Controlled release solid dispersion (CASD) is a novel approach with the aim to increase bio-availability of poorly soluble drugs along with reduction of frequency of dosing and cumulative dose [ 7 ]. The interplay between formulation components and process variables significantly influences the therapeutic efficacy and safety of the final product. It serves as a surrogate for in vivo performance, making it essential for ensuring therapeutic efficacy. Among the tools used to characterize and control formulation behaviour, discriminatory dissolution medium identifies formulation variations that may impact bioavailability [ 8 ]. This technique is not only capable of differentiating between subtle changes in formulation attributes or process conditions, but it also provides a predictive link between in vitro testing and in vivo performance [ 9 ]. This aids in establishing Critical Quality Attributes (CQAs) of CASDs where drug release mechanisms are governed by interplay of the polymer and the amorphous drug along with their ratio, as well as with the plasticizer [ 10 ]. This study focuses on integrating discriminatory dissolution testing within a QbD-based development for Apremilast CASD systems. It aids in tracking the changes in the product performance in response to factors like change in method of production or composition before moving to in vivo studies. Apremilast is a poorly soluble drug and has absolute bioavailability of 70% and half-life of 5–7 h [11–13]. Apremilast CASD was conceptualized with once a day dose with increased bioavailability and reduction of total cumulative daily dose instead of the current therapeutic regimen with higher dosing frequency and overall dose. Dissolution behavior is highly dependent on the properties of Drug, in this case, Apremilast, the nature of the polymers, Kollidon VA64 and Methocel K100 LVCR, and manufacturing process parameters which affect surface area exposure, disintegration and subsequent release. Each of these factors must be optimized to achieve a consistent and predictive dissolution profile. By identifying and understanding the influence of Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs), the goal is to ensure a robust, reproducible result with optimal performance [14]. This approach not only supports regulatory expectations but also fosters innovation in designing more effective drug delivery systems. Thus, the formulation variables and dissolution method for the prototype formulation was chosen to ensure tailored dissolution to subsequently offer a formulation with reduced dose as well as frequency of administration [15]. This selection process involved manipulating different parameters of formulation development and discriminatory dissolution development through two separate DoEs. Factors such as the levels of dispersion polymer, rate controlling polymer, plasticizer for the formulation development and volume of the dissolution media, agitation speed, type of apparatus (either paddle or basket), and the pH of the media were considered for the development of discriminatory dissolution media development [16]. Media pH was chosen based on highest solubility of amorphous solid dispersion and maintenance of sink conditions during dissolution. The dissolution apparatus was chosen based on the comparative dissolution profile between USP-1 and USP 2 based on complete release and least possible % RSD [17]. Finally, the chosen dissolution media is rigorously tested to assess its discriminatory power to ensure that the dissolution method is robust and capable of distinguishing between minor formulations and process changes effectively [18]. 1.1 Quality Target Product Profile (QTPP) and Risk Assessment The QTPP serves as an overview of the key quality attributes expected of a drug product, ensuring that it meets the necessary standards for safety and efficacy. This profile is a crucial component of a QbD strategy and lays the groundwork for product development. In the context of New Drug Applications (NDAs), it is important to establish these targets early in the development phase, considering the drug substance's properties, product rationale and dosing frequency, as well as the target patient demographic. By planning with the end goal in mind, developers can create a resilient formulation and manufacturing process, supported by a solid control strategy that guarantees reproducible performance [19–23]. CQAs are defined as properties—whether physical, chemical, biological, or microbiological—that must remain within specific limits to ensure the desired quality of the product. The selection of CQAs from the QTPP is influenced by the risk analysis. All quality attributes represent essential targets for the drug product and should be met through an effective quality management system, along with suitable formulation and process design to develop an effective control strategy. The current work deals with formulation development with major emphasis upon dissolution profile as the CQA [24–25]. The drug release investigation and release kinetics prediction showed a 24 h release profile as designed for once a daily dose. Apremilast CASD serves the dual purpose of solubility and bioavailability enhancement with reduced daily dose and side effects. The above characteristics increase dose tolerance of CASD to patients [21]. 1.2 Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs) : The CMAs and CPPs evaluated in this study, along with their impact on dissolution and control strategies for Apremilast CASD are summarized in Table 1 . These high-risk ranking variables were further studied and optimized to define the design space. Within the design space, the changes of CPPs and CMAs are acceptable without compromising the product quality of CASD. Manufacturing of a CASD involves interplay of multiple factors with respect to materials as well as process parameters which in turn influence the product performance. The selection of dissolution parameters is essential to derive the correct dissolution outcome. The following section discusses development, dissolution, determination of dissolution kinetics and discriminatory power of selected dissolution for Apremilast CASD [26]. Table 1 Dissolution Risk Assessment & Control strategy of Critical Variables Critical Variable Effect on Dissolution Control Strategy Dosage form type (Controlled release) Matrix forms impact release profile and sensitivity to dissolution condition For tablet dosage form USP-2 was selected and after dissolution development the same was finalized Tablet shape Surface area and orientation in vessel influence wettability and hydrodynamic interaction Tablet shape was round and 8 mm round punch was finalized during product development Release mechanism Diffusion, erosion, or osmotic systems demand tailored dissolution conditions Methocel K100 LVCR has diffusion controlled followed by erosion. During formula optimization the optimum level also finalized. Analyst variability (Men/Analyst) Manual handling, sampling, and interpretation can introduce inconsistency Train analysts thoroughly; use SOPs and automation where feasible Dissolution parameters/conditions Agitation speed, medium pH, and volume influence hydrodynamics and drug release patterns Optimize and validate conditions for adequate discriminatory power for Apremilast CASD Material & Process Attributes Risk Assessment - Effect on Critical Quality Attributes (Dissolution) Control Strategy Critical Material Attributes Apremilast - Property Apremilast melting point (156.1℃) is very important for HME process and above melting points only active ingredient-polymer molecular level mixing is possible. Strong active ingredient-polymer interaction, especially molecular level interaction and bonding are helpful to improve stability of HME-ASD. So, the impact of melting point on dissolution is critical. The risk is high. A processing temperature range of 40 to 160°C was maintained in the HME zones, exceeding the melting point of Apremilast, to promote molecular-level mixing beTween® the active ingredient and the polymer, thereby enabling full conversion to the amorphous state. The absence of particulate matter in the extrudates and the observation of a single-phase system confirmed uniform mixing at the molecular level. Level of Solid dispersion polymer (Kollidone VA 64) The concentration of Kollidon VA 64 plays a critical role in stabilizing the solid dispersion of Apremilast. Without achieving the appropriate molecular-level interaction beTween® Apremilast and Kollidon VA 64 at the optimal ratio, complete conversion to the amorphous form—and consequently, enhancement of solubility—cannot be effectively attained. 1:2 ratio of Apremilast: Kollidone VA 64 was selected as the optimal formulation due to its superior solubility and stability in the Apremilast: Kollidone VA 64 solid dispersion. Alternative ratios demonstrated reduced solubility enhancement and exhibited the presence of particulate matter in the hot-melt extrudates, suggesting a lack of molecular-level mixing. Therefore, the 1:2 ratio was confirmed as the most effective Level Controlled release polymer (Methocel K100 LV CR) The concentration of Methocel K100 LVCR plays a pivotal role in modulating the dissolution rate. Higher levels tend to slow down dissolution, whereas lower concentrations lead to an increased rate of dissolution Methocel K100LVCR concentration of 23.75% w/w was identified as optimal, achieving both a suitable dissolution rate and complete dissolution within 24 hours. Concentrations below this level led to a faster release but did not sustain dissolution, while higher concentrations resulted in a slower release and incomplete dissolution. Critical Process Parameters Hot Melt Extrusion Parameters Zone temperature has a pivotal role to ensure active ingredient-polymer miscibility at the molecular level and to ensure complete amorphous conversion. A process temperature above the melting point of active ingredient molecules ensures complete active ingredient miscibility and stable ASD. Based on the degree of active ingredient-polymer miscibility, amorphization, kinetic solubility and dissolution rate differs. Processing temperature beTween® 40°C and 160°C was applied during the hot-melt extrusion process, surpassing the melting point of Apremilast to facilitate thorough interaction beTween® the drug and polymer at the molecular level. This approach ensured complete amorphization, as evidenced by the lack of visible particulates and the formation of a single-phase extrudate, indicating homogenous molecular mixing. Tablet compression Force Compression force significantly influences tablet hardness that affects the rate and extent of drug dissolution. As compression force increases hardness also increases, dissolution may slow due to reduced tablet disintegration, whereas decreased compression force results lower hardness often facilitates faster and more complete dissolution. Apremilast CASD tablets with compression force up to 8–10 tons results hardness beTween® 8 to 11 kP was found to provide an optimal balance, achieving both an appropriate dissolution rate and complete drug release. 2. Materials and Methods 2.1 Materials Apremilast was taken as a gift sample from M/s Hetero Labs, India. Kollidon® VA 64 from M/s BaSF, Triethyl citrate from M/s Vertellus, Klucel® LF from M/s Ashland, Methocel® K100 LVCR from M/s Dow, Colloidal silicon dioxide (Aerosil® 200) from M/s Evonik, microcrystalline cellulose from M/s FMC Biopolymer and Stearic Acid from M/s Nitika pharmaceuticals were obtained. 2.2 Methods 2.2.1 Development of Apremilast Amorphous Solid Dispersion Different ratios (1:1, 1:2, 1:3, 1:4) of Apremilast and Kollidon® VA 64 and HPMC-AS with 10.5% w/w Klucel™ LF (hydroxypropylcellulose, low viscosity grade) combined to enhance film-forming and mechanical properties in dispersions, 0.9%w/w Aerosil® (colloidal silicon dioxide) as a glidant and stabilizer to improve powder flow and prevent agglomeration and 3.67% w/w TEC (triethyl citrate) as plasticizer that improves processability in HME and enhances flexibility of polymer matrices-were taken for hot melt extrusion. HME (Thermofisher Scientific, EuroLab 16 XL Twin-Screw Extruder, 100rpm, 40:1 L/D ratio XL 553–5020) feeder (with feeder rpm from 2–4) and torque 37–42% maintaining ten zone temperature from 45° to 160°C (Zone 1–35°C, Zone 2–45°C, Zone 3–95°C, Zone 4- 110°C, Zone5- 145°C, Zone 6-150°C, Zone 7-160°C, Zone 8-160°C, Zone 9-155°C, Zone 10–35°C) [20]. The final extrudes were milled with a 0.5 mm screen in a co-mill (The SLS - Scalable Lab System, Quadro). The formulation trials have been added along with the supplementary information. Both extrudates were subjected to solubility evaluation across the physiological pH range [ 27 – 30 ]. 2.2.2 Solubility of Apremilast Amorphous Solid Dispersion An excess amount of the Apremilast solid dispersion was added to a fixed volume of the chosen dissolution medium in a sealed container. The sealed mixtures were continuously stirred at a constant temperature, typically 37.0 ± 0.5°C, for 24 hours to ensure saturation. After equilibrium was attained, the suspension was filtered (using a 0.45 µm membrane filter) to separate the undissolved solid from the saturated solution. The concentration of Apremilast in the clear supernatant is quantified by HPLC. Different ratios of Apremilast and Kollidon® VA 64 solid dispersion HME extrudes and Apremilast and HPMC-AS solid dispersion HME extrudes were taken for solubility study across physiological pH [ 30 ]. Solvents used were 0.1N HCl, 0.01N HCl, 0.001N HCl, water, pH 4.5 acetate buffer, pH 6.8 phosphate buffer, pH 7.2 phosphate buffer, pH 7.5 phosphate buffer. 2.2.3 Formulation Development of Apremilast CASD Tablets The extrudes were milled with 0.5 mm screen in co-mill and mixed with Methocel® K100 LVCR, microcrystalline Cellulose and Aerosil® 200 after passing through ASTM #30 mesh (Bectochem) and blend for 10 minute in a double cone blender (SAAN Engineering) with 35% occupancy. Stearic acid was mixed into the blend and lubricated for 5 min in the same blender with 36% occupancy. The final lubricated blend was compressed into tablets in a compression machine (Cadmach, CMB-4-017). A central composite design (CCD) was employed to evaluate the impact of critical material attributes on dissolution performance [ 31 ]. The selected excipients—Kollidon® VA 64, Klucel™ LF, Triethyl Citrate (TEC), and Hypromellose (Methocel™ K100 LVCR)—were investigated as independent variables, with dissolution profiles at 2, 6, and 24 hours serving as response parameters (Supplementary Information). Dissolution is a critical quality attribute (CQA) because it directly influences drug release and bioavailability, especially in oral solid dosage forms. Ishikawa diagram correctly describes the variables involved for dissolution of final dosage form (Fig. 1 ) [32–38]. The selection of dissolution parameters like, surfactant concentration, agitation, media volume, pH, apparatus are very important in order to finalize the discriminatory dissolution condition [ 39 ]. The risk assessment and control strategy for variables affecting dissolution are summarized in Table 1 [ 40 ]. The Table 1 elaborates how key CMAs and CPPs influence dissolution, and outlines control strategies to ensure batch-to-batch consistency and robust product performance. 2.2.4 Discriminatory Dissolution Method Development of Apremilast CASD Tablets The dissolution method for the prototype formulation is chosen to ensure the best suitable rate and extent of dissolution [ 41 ]. This selection process involves manipulating different parameters such as the volume of the dissolution media, agitation speed, type of apparatus (either paddle or basket), and the pH of the media. Media pH was chosen based on highest solubility of amorphous solid dispersion so that sink conditions can be maintained during dissolution. Dissolution apparatus was chosen based on the comparative dissolution profile between USP-1 and USP 2. The choice between the two apparatus depends on the dosage form, its release characteristics, and regulatory guidelines to ensure accurate dissolution testing, supporting bioavailability and therapeutic efficacy [ 42 ]. 2.2.4.1 Selection of Surfactant Concentration Initially, as per practice, USP apparatus II was chosen for tablet dosage form to assess the effect of surfactant concentration. From the solubility graph, the maximum solubility was observed in pH 4.5 Acetate buffer. Further the dissolution study was conducted in pH 4.5 acetate buffer with media volume 900 ml and paddle speed 75 rpm for initial evaluation by varying surfactant, Tween®80 concentration from 0 to 2% [ 43 ]. 2.2.4.2 Selection of Agitation Speed Agitation speed in dissolution testing directly influences the hydrodynamics of the dissolution medium, affecting the drug release rate and dissolution behaviour. Higher agitation speeds create greater turbulence, enhancing the convective flow around the dosage form and improving drug diffusion from its surface into the surrounding medium. This can accelerate the dissolution process, especially for poorly soluble drugs [ 44 ]. However, excessive agitation can introduce higher shear forces, potentially altering the physical structure of sensitive formulations, such as soft capsules or extended-release tablets, leading to deviations in the intended release profile. Conversely, slower agitation speeds reduce turbulence, providing a gentler dissolution environment that may be preferable for formulations requiring controlled or slow release. Thus, the optimal agitation speed must balance efficient drug release with the preservation of the dosage form’s integrity, ensuring accurate and reproducible dissolution testing. 50, 75, 100 rpm were chosen to access the dissolution behaviour. [ 45 ]. 2.2.4.3 Selection of Dissolution Apparatus Effect of dissolution apparatus was also evaluated keeping other dissolution parameters same like 1% w/w Tween®80 in 50 mM Sodium Acetate Buffer pH 4.5, 900 ml, 75 rpm [ 46 ] 2.2.4.4 Selection of Media Volume For poorly soluble drugs, maintaining sink conditions—where the volume of dissolution medium should be large enough to prevent the drug concentration from exceeding its solubility—is critical for accurate dissolution testing. Appropriate media volume ensures that the drug remains in a supersaturated state, promoting continuous dissolution. Ensuring an appropriate volume helps to simulate realistic gastrointestinal conditions and provides reliable data for poorly soluble drugs [ 47 ]. The effect of media volume on dissolution of Apremilast CASD was evaluated as mentioned below Table 2 . 2.2.4.5 Selection of Media pH From the solubility data highest solubility was achieved in pH 4.5 acetate buffer. So initially pH 4.5 acetate buffer was selected for dissolution development. Additionally, in other pH the dissolution behaviour was examined keeping optimised dissolution parameter 1% w/w Tween®80 in, 900 ml, 75 rpm USP II Apparatus (Paddle) [ 48 – 54 ] 2.2.5 Design of Experiments The media pH 4.5 was selected based on the highest solubility of Apremilast CASD and USP II was chosen based on its suitability for tablet dosage form and more uniform release observed compared to USP I. The design of experiments was performed using three critical variables. The experimental design and response specifications are summarized in Table 2 [ 55 – 56 ]. Table 2 Design Summary Factors 3 Runs 11 Replicates 1 Center pts (total) 3 Tool Minitab Variables Responses Factors Lower Limit Higher Limit Responses Specification Volume of Media (ml) 800 1000 %Dissolution at 2h 10–35% Agitation Speed (rpm) 50 100 %Dissolution at 6 h 40–60% Surfactant Level (% w/w) 0.5 1.5 %Dissolution at 24 h NLT 80% 2.2.6 Setting Dissolution Specification-Apremilast CASD Tablets As per USP [ 49 ] and CDER [ 41 ] and EMA guidance [ 51 ] on modified release products, minimum three time points should be included in the specification for controlled release formulation- A loading or initial point (typically 20–30% release), intermediate point (around 50% release) and final time point (at least 80% release). The same was adopted in the present study. 2.2.7 Dissolution Kinetics The dissolution profile of the formulation was analysed using several model-dependent release kinetics approaches, including zero-order, first-order, Higuchi, Hixson–Crowell, and Korsmeyer–Peppas models [ 52 – 54 ]. These models were applied to the experimental data to determine the most suitable mechanism of drug release. 2.2.8 Discriminatory Power of Selected Dissolution The discriminatory capability of the dissolution method refers to its ability to identify changes in the drug product. Proving the method’s discriminatory power is both challenging and essential, especially when monitoring active pharmaceutical ingredient (API) or formulation factors that are crucial for the optimal performance of poorly soluble compounds. In an ideal scenario, the dissolution test conditions should be sensitive enough to detect changes in the product that could impact its biopharmaceutical performance [ 56 – 57 ]. The ability of a dissolution method to discriminate is crucial in determining whether it can detect changes in critical material attributes (CMAs) and critical process parameters (CPPs) that might influence the drug's bioavailability [ 58 ]. The selected dissolution media was tested for the discriminatory potential by changing the polymer concentration. 3. Results The physical characterization of Apremilast CASD has been included in the supplementary information. 3.1 Solubility of Apremilast Solid Dispersion The solubility of Apremilast solid dispersion prepared with different Apremilast: Kollidon VA 64 ratios across physiological pH conditions is shown in Fig. 2. The study revealed (Fig. 2) that the solid dispersion of Apremilast with Kollidon VA 64 at a 1:2 ratio exhibited the highest solubility across all tested pH conditions, outperforming other ratios as well as formulations with HPMC-AS. Consequently, the API–Kollidon VA 64 (1:2) solid dispersion was selected for further development [59–60]. 3.2 Dissolution of Apremilast CASD tablets Tablets with Hypromellose (Methocel K100 LVCR) at 20% w/w produced a faster release rate of Apremilast compared with 23.75% w/w, whereas increasing the level to 27.5% w/w led to a slower release and incomplete drug release over 24 hours. Tablets Methocel K4M at 3.75% and 6.25% w/w, as well as Methocel K100M at 2.5% and 5% w/w, also exhibited slower release rates with incomplete release up to 24 hours. Similarly, the hydrophobic polymer ethyl cellulose (7 cps) at 2.5% and 5% w/w resulted in incomplete drug release. Polymer concentrations below 2.5% w/w were found to be difficult to uniformly disperse within the blend, potentially leading to dissolution variability. Among all formulations evaluated, Methocel K100 LVCR at 23.75% w/w demonstrated the most optimal controlled-release profile over a 24-hour period (Supplementary information) 3.4 Discriminatory Dissolution Development 3.4.1 Surfactant Concentration The effect of surfactant concentration on the dissolution behavior of Apremilast CASD indicated that 1% w/w Tween® 80 provided optimal dissolution performance (Fig. 3.). Lower concentrations led to incomplete release, while higher concentrations increased variability. These findings are consistent with the literature [61–62]. 3.4.2 Agitation Speed Agitation speed pf 75 rpm yielded complete release with low % RSD, outperforming 50 rpm (slow, variable) and 100 rpm (fast, variable) [63–64] as illustrated in Fig. 3. 3.4.3 Dissolution Apparatus USP Apparatus II (paddle) showed uniform and complete drug release compared to USP Apparatus I (basket) [65–66] as illustrated in Fig. 3. 3.4.4 Media Volume The effect of dissolution media volume on the release of Apremilast CASD is illustrated in Fig. 3. 3.4.5 Media pH The effects of media pH, surfactant concentration, agitation speed, dissolution apparatus, media volume, on the dissolution behavior of Apremilast CASD are illustrated in Fig. 3. pH 4.5 acetate buffer confirmed optimal drug release with low variability. 3.5 Design of Experiments For dissolution at 2 h and 6h, all main variable and interaction effects were significant (p < 0.05). Whereas, for dissolution at 24 h, agitation and surfactant level were significant however volume of media and interaction of volume and agitation speed was not significant within the studied range [46–47]. Statistical analysis (supplementary information) confirmed significance of media volume, agitation, and surfactant level at 2 h and 6 h (p < 0.05). At 24 h, agitation and surfactant remained significant, while media volume and its interaction with agitation were found to be insignificant [55–56]. The influence of critical dissolution variables and the defined design space are depicted through contour plots is shown in Fig. 4. The impact of main effect plots, design space 2 h (10–35%), 6 h (40–60%), 24 h (≥ 80%) have been included in the supplementary information. From the main effect graph, at 2h and 6 h,all main effects (media volume, agitation and surfactant level) have a positive effect on dissolution, if the main effect level increases the dissolution will also increase [62]. At 24 h, agitation and surfactant level have strong positive effect whereas media volume has very slight positive effect. From the contour plot, the design space can be selected based on specification criteria of % dissolution at 2h should be 10–35%; at 6 h should be 40–60% and at 24 h should be NLT 80%. Finally, 1% w/w Tween® 80 in 900 ml pH 4.5 acetate buffer, agitation speed of 75 rpm, USP 2 apparatus were selected for dissolution of Apremilast CASD. 3.6 Dissolution Specification – Apremilast CASD Specifications were finalized (Table 2) based on optimized parameters and regulatory guidance [49–50]. The finalized dissolution specifications for Apremilast CASD tablets complied with the decided specifications. Tabular representation of the same can be found in the supplementary information. 3.7 Dissolution Kinetics The Hixson–Crowell model proved to be the best fit (R² = 0.9969) for the dissolution profile, as shown in Fig. 5, indicating erosion-controlled drug release [52–54 and 67–70]. 3.8 Discriminatory Power The selected medium effectively discriminated against formulation variables such as polymer concentration and process variations like hardness. Tablet hardness and Methocel® K100 LVCR concentration critically influenced dissolution. The discriminatory nature of the selected dissolution method under varying formulation and process conditions is tabulated in Table 3. Table 3: Discriminatory nature of selected dissolution media for Apremilast CASD Discriminatory nature of selected dissolution media Time (h) Specification Limit 1 % w/w Tween® 80 in 50 mM Sodium Acetate Buffer pH 4.5, 900 ml, USP-2, 75 rpm Optimum Formulation (hardness 8-11 kp) Lowering level (-20 % w/w) Methocel K100 LVCR Low Hardness (5-7 kp) Avg (min - max) % RSD Avg (min - max) % RSD Avg (min - max) % RSD 1 7 ± 8.2 3 ± 75.42 19 ± 17.68 2 10 - 35 22 ± 5.8 7 ± 24.94 33 ± 10.52 4 35 ± 3.6 18 ± 19.38 47 ± 7.03 6 40 - 60 45 ± 2.1 31 ± 6.13 61 ± 4.08 8 62 ± 6.1 53 ± 3.56 77 ± 5.4 12 77 ± 7.9 65 ± 3.34 84 ± 2.85 16 88 ± 2.4 76 ± 3.05 92 ± 2.48 24 NLT 80 98 ± 2.3 88 ± 4.89 99 ± 2.41 4. Discussion The development of a discriminatory dissolution method for Apremilast CASD was achieved by QbD framework, ensuring systematic optimization of formulation and process variables. Solubility profiling across physiological pH confirmed that Apremilast: Kollidon® VA 64 (1:2) extrudes exhibited highest solubility in pH 4.5 acetate buffer, justifying its selection for dissolution media to maintain sink conditions and ensure consistent release. Surfactant concentration emerged as a critical variable, with 1% Tween® 80 delivering optimal dissolution performance—balancing release rate and minimizing % RSD. Lower concentrations led to incomplete release, while higher levels introduced variability [ 71 – 72 ]. Agitation speed was equally influential; 75 rpm provided complete release with low variability, outperforming both slower (50 rpm) and faster (100 rpm) conditions [ 63 – 64 ]. Among apparatus types, USP-II (paddle) demonstrated superior performance over USP-I (basket), offering uniform and complete release profiles aligned with regulatory expectations for tablet dosage forms [ 73 – 74 ]. Media volume was another determinant of robustness of the discriminatory dissolution medium. A volume of 900 ml ensured sink conditions and minimized variability, supporting reproducible performance. DoE approach validated the statistical significance of surfactant level, agitation speed, and media volume—particularly at early time points (2 h and 6 h), while at 24 h, agitation and surfactant remained dominant influencers. Contour plots and main effect helped define a design space that supports regulatory flexibility and batch-to-batch consistency [ 75 ]. Kinetic modeling revealed that the Hixson–Crowell model best described the release mechanism (R² = 0.9969), indicating erosion-controlled dissolution with uniform tablet size reduction. This aligns with the intended controlled-release profile of Apremilast CASD, designed for once a day dosing and reduced cumulative dose [ 76 – 78 ]. The discriminatory power of the selected method was evaluated by altering critical material attributes (e.g., Methocel®K100 LVCR concentration) and process parameters (e.g., tablet hardness). Increased levels of Methocel® led to slower release and failure to meet dissolution specifications at 1 h and 6 h, confirming the method’s sensitivity to formulation changes. This validates its utility in routine quality control and formulation development, ensuring robust performance and regulatory compliance [ 79 – 80 ]. In summary, the optimized dissolution method—1% Tween® 80 in 900 ml pH 4.5 acetate buffer at 75 rpm using USP-II—demonstrated reproducibility, sensitivity, and alignment with controlled-release kinetics. 5. Conclusion Apremilast CASD was successfully developed by HME using DoE. The dissolution method for Apremilast, was optimized with respect to media volume, agitation, pH, and apparatus to provide a discriminatory dissolution medium. Controlled-release kinetics aligned with the Hixson–Crowell model, ensuring uniform tablet erosion. Experimental design statistically validated the discriminating power of the medium across formulations. A QbD-DoE enabled discriminatory dissolution medium provides an adequate platform to gauge the qualitative as well quantitative impact exerted by the process these variables, involved in formulation of a CASD thereby allowing a sustainable and robust formulation development. Abbreviations QbD : Quality by Design QTPP : Quality Target Product Profile CQA : Critical Quality Attribute CASD : Controlled-Release Amorphous Solid Dispersion ASD : Amorphous Solid Dispersion HME : Hot-Melt Extrusion DOE : Design of Experiments CMA : Critical Material Attribute CPP : Critical Process Parameter OFAT : One Factor At a Time FDA : Food and Drug Administration CDER : Center for Drug Evaluation and Research EMEA : European Medicines Agency (now formally EMA) RSD : Relative Standard Deviation Declarations Acknowledgement Authors are grateful for the gift sample of Apremilast from M/s Hetero Labs. We would like to acknowledge Department of Science and Technology (SR/FST/College-054/2017) for the infrastructure. Author contributions Credit: Sandipan Roy: Formal analysis, Investigation, Writing; Apoorva Phadke- Conceptualization, writing, review & editing. Nehal Sarvaiya – Review and editing Sujata Sawarkar & Vaishali Y. Londhe: Conceptualization, Supervision, Writing – review & editing. Statements and Declarations Conflict of Interest: The authors declare no conflict of interest. Funding The author(s) reported there is no funding associated with the work featured in this article. Data Availability Statement The authors declare that all the supporting data are con­tained within the paper. Future Scope: PK-PD studies with IVIVC correlation References Lee MR, Hsieh KS, Gage WB, Tillman AJ, Carlin JS. The role of quality by design (QbD) in pharmaceutical development and regulatory submissions. Int J Pharm. 2009;367:52–61. Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000;50:47–60. Bhujbal SV, Mitra B, Gong Y, Agrawal A, Karki S, Taylor LS, Kumar S, Zhou QT. Pharmaceutical amorphous solid dispersion: a review of manufacturing strategies. Acta Pharm Sin B. 2021;11(8):2505–36. https://doi.org/10.1016/j.apsb.2021.05.014 . 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Ashokraj Y, Daroi A, Gupta R, Khanolkar A, Kulkarni A, Laud S, Pokale M, Shedge S, Date P. Discriminatory dissolution method development and validation of etoricoxib tablets. Dissolution Technol. 2016;May:6–13. Chen H, Wang R, McElderry JD. Discriminative dissolution method development through an aQbD approach. AAPS PharmSciTech. 2023;24:255. https://doi.org/10.1208/s12249-023-02692-8 . Higuchi T, Connors KA. Phase solubility techniques. Advances in Analytical Chemistry and Instrumentation. New York: Wiley Interscience; 1965. pp. 117–212. Yang L, Wu P, Xu J, Xie D, Wang Z, Wang Q, Chen Y, Li CH, Zhang J, Chen H, Quan G. Correction to: development of Apremilast solid dispersion using TPGS and PVPVA with enhanced solubility and bioavailability. AAPS PharmSciTech. 2021;22(5):176. https://doi.org/10.1208/s12249-021-02046-2 . Chen LR, et al. Dissolution behavior of a poorly water-soluble compound in the presence of Tween® 80. Pharm Res. 2003;20:797–801. Braun RJ, Parrott EL. Influence of viscosity and solubilization on dissolution rate. J Pharm Sci. 1972;61(2):175–8. Medina-López R, Guillén-Moedano S, Hurtado M. In vitro release studies of furosemide reference tablets: influence of agitation rate, USP apparatus, and dissolution media. ADMET DMPK. 2020;8(4):411–23. https://doi.org/10.5599/admet.801 . Phillips DJ, Pygall SR, Cooper VB, Mann JC. Overcoming sink limitations in dissolution testing: a review of traditional methods and the potential utility of biphasic systems. J Pharm Pharmacol. 2012;64:1549–59. Sirasitthichoke C, Patel S, Reuter K, Hermans A, Bredael G, Armenante PM. Computational determination of hydrodynamics in the USP dissolution testing Apparatus 1 (rotating basket). Chem Eng Sci. 2023;280:118946. Lindfors L, Jonsson M, Weibull E, Brasseur J, Abrahamsson B. Hydrodynamic effects on drug dissolution and deaggregation in the small intestine: a study with felodipine as a model drug. J Pharm Sci. 2015;104(9):2969–76. Fotaki N, Brown W, Kochling J, Chokshi H, Miao H, Tan K, Gray V. Rationale for selection of dissolution media: three case studies. Dissolution Technol. 2013;Aug:6–11. Mudie DM, Samiei N, Marshall DJ, Amidon GE, Bergström CAS. Selection of in vivo predictive dissolution media using drug substance and physiological properties. AAPS J. 2020;22(2):34. https://doi.org/10.1208/s12248-020-0417-8 . Ge K, Paus R, Penner V, Sadowski G, Ji Y. A novel theoretical strategy for predicting dissolution kinetics and mechanisms of pharmaceuticals in complex biorelevant media. Int J Pharm. 2023;648:123594. https://doi.org/10.1016/j.ijpharm.2023.123594 . Preiss FN, Chopra AS, Khandelwal KP. Analysis and validation of dissolution methodology for QbD. Int J Pharm. 2006;315:18–25. Bhatia AT, Patel SV, Shah AP, Prajapati PR. Application of statistical design of experiment for optimization of dissolution rate in tablet formulations. Pharm Dev Technol. 2017;22:694–702. Wassberg RJ, Engdahl WG. Discriminatory nature of dissolution testing and its implications for drug development. Pharm Technol. 2010;34:1–8. Spinks DL, Peters RD, Leventhal EP. A novel application of quality by design (QbD) in pharmaceutical development. J Pharm Innov. 2010;5:101–12. McCracken TM, Duffin AS, Sandle SP. A QbD approach to dosage form development: practical examples. Int J Pharm. 2013;455:42–9. Patel PPD, Pandit TG, Ray AR. QbD in pharmaceutical development: case studies for optimizing dissolution testing for complex drug products. Int J Pharm Sci. 2012;13:2305–12. Amidon MJ, Vyas RV, Esposito DR, Patel AN, Dvorkin KS. Dissolution development by QbD: a case study approach to understanding dissolution performance. Int J Pharm. 2013;451:1–8. Khan CL, Niazi JPKP. Dissolution testing: its role in formulation development and quality control. Int J Pharm Sci. 2005;12:45–55. Sinko PJ, Phipps LA, Finley TD. Principles of drug absorption and dissolution: a QbD perspective. Drug Dev Ind Pharm. 2002;28:467–75. Moore AW, Boulas DC, Furgeson KE. The impact of dissolution testing on drug product development: a case study approach. AAPS J. 2014;16:765–74. Zhang BBKM, Farid AJ. Application of QbD in dissolution testing and its impact on drug development. Int J Pharm. 2012;424:154–63. Additional Declarations No competing interests reported. Supplementary Files SupplementaryInformation.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8916904","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":629597954,"identity":"6dd14f82-8112-4201-8cc5-369ea6108bf7","order_by":0,"name":"Sandipan Roy","email":"","orcid":"","institution":"SVKM’s Dr. Bhanuben Nanavati College of Pharmacy","correspondingAuthor":false,"prefix":"","firstName":"Sandipan","middleName":"","lastName":"Roy","suffix":""},{"id":629597956,"identity":"1d1ca792-def8-43f2-9fdb-985d062ec06b","order_by":1,"name":"Apoorva Phadke","email":"","orcid":"","institution":"SVKM’s Dr. Bhanuben Nanavati College of 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2","display":"","copyAsset":false,"role":"figure","size":315693,"visible":true,"origin":"","legend":"\u003cp\u003eSolubility of amorphous solid dispersion of different ratio of Apremilast-Kollidone VA 64 and Apremilast-HPMC-AS\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8916904/v1/4b2ec815e7edfb0fcd979ff4.jpg"},{"id":108183060,"identity":"a0ce77ee-5b1c-43f9-848e-e2fe919273bb","added_by":"auto","created_at":"2026-04-30 08:59:46","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":123047,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEffect of Surfactant Concentration, agitation speed, dissolution apparatus, media volume, pH, formulation and process changes on dissolution of Apremilast CASD\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8916904/v1/abae7066cc68c0498ce63ff3.jpg"},{"id":108182257,"identity":"eb4bbb00-f0e5-4ce4-8fd3-dc0545d323aa","added_by":"auto","created_at":"2026-04-30 08:59:17","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":95202,"visible":true,"origin":"","legend":"\u003cp\u003eContour Plot of D2, D6, D24 vs Surfactant level (%) vs Agitation speed (rpm)\u003c/p\u003e","description":"","filename":"Picture4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8916904/v1/b0fb9f79361abc406d5334fd.jpg"},{"id":108142578,"identity":"66439dfe-87b2-45a1-b293-0fc57e955e6f","added_by":"auto","created_at":"2026-04-29 19:50:00","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":11230,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHixson-Crowell model graph of Apremilast CASD\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Picture5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8916904/v1/ce03ead8704bd27304300dd3.jpg"},{"id":108183542,"identity":"f442b761-beb9-4c38-9537-5e161c67852a","added_by":"auto","created_at":"2026-04-30 09:02:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1082721,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8916904/v1/75cbc7d2-3f21-4ab1-bc6c-2059d09dc35a.pdf"},{"id":108142573,"identity":"06d8eba8-525c-4d11-a71e-e05d006a8abd","added_by":"auto","created_at":"2026-04-29 19:50:00","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":1376184,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryInformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-8916904/v1/52ea942e3f32e5c4be44f532.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Formulation Development and Design of Discriminatory Dissolution Medium for Controlled Release Amorphous Solid Dispersion of Apremilast for Once A Day Administration: A QbD Approach","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eIn pharmaceutical development, adopting a QbD approach allows thorough understanding of the formulation and manufacturing process [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR21\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. For Controlled Release (CR) formulations based on Amorphous Solid Dispersions (ASDs), this framework becomes especially essential due to the process as well as material variables, their interplay and its impact on stability and performance of the delivery system [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Controlled release solid dispersion (CASD) is a novel approach with the aim to increase bio-availability of poorly soluble drugs along with reduction of frequency of dosing and cumulative dose [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The interplay between formulation components and process variables significantly influences the therapeutic efficacy and safety of the final product. It serves as a surrogate for in vivo performance, making it essential for ensuring therapeutic efficacy. Among the tools used to characterize and control formulation behaviour, discriminatory dissolution medium identifies formulation variations that may impact bioavailability [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This technique is not only capable of differentiating between subtle changes in formulation attributes or process conditions, but it also provides a predictive link between in vitro testing and in vivo performance [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. This aids in establishing Critical Quality Attributes (CQAs) of CASDs where drug release mechanisms are governed by interplay of the polymer and the amorphous drug along with their ratio, as well as with the plasticizer [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study focuses on integrating discriminatory dissolution testing within a QbD-based development for Apremilast CASD systems. It aids in tracking the changes in the product performance in response to factors like change in method of production or composition before moving to in vivo studies. Apremilast is a poorly soluble drug and has absolute bioavailability of 70% and half-life of 5\u0026ndash;7 h [11\u0026ndash;13]. Apremilast CASD was conceptualized with once a day dose with increased bioavailability and reduction of total cumulative daily dose instead of the current therapeutic regimen with higher dosing frequency and overall dose. Dissolution behavior is highly dependent on the properties of Drug, in this case, Apremilast, the nature of the polymers, Kollidon VA64 and Methocel K100 LVCR, and manufacturing process parameters which affect surface area exposure, disintegration and subsequent release. Each of these factors must be optimized to achieve a consistent and predictive dissolution profile.\u003c/p\u003e \u003cp\u003eBy identifying and understanding the influence of Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs), the goal is to ensure a robust, reproducible result with optimal performance [14]. This approach not only supports regulatory expectations but also fosters innovation in designing more effective drug delivery systems. Thus, the formulation variables and dissolution method for the prototype formulation was chosen to ensure tailored dissolution to subsequently offer a formulation with reduced dose as well as frequency of administration [15]. This selection process involved manipulating different parameters of formulation development and discriminatory dissolution development through two separate DoEs. Factors such as the levels of dispersion polymer, rate controlling polymer, plasticizer for the formulation development and volume of the dissolution media, agitation speed, type of apparatus (either paddle or basket), and the pH of the media were considered for the development of discriminatory dissolution media development [16]. Media pH was chosen based on highest solubility of amorphous solid dispersion and maintenance of sink conditions during dissolution. The dissolution apparatus was chosen based on the comparative dissolution profile between USP-1 and USP 2 based on complete release and least possible % RSD [17]. Finally, the chosen dissolution media is rigorously tested to assess its discriminatory power to ensure that the dissolution method is robust and capable of distinguishing between minor formulations and process changes effectively [18].\u003c/p\u003e \u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003e1.1 Quality Target Product Profile (QTPP) and Risk Assessment\u003c/h2\u003e \u003cp\u003eThe QTPP serves as an overview of the key quality attributes expected of a drug product, ensuring that it meets the necessary standards for safety and efficacy. This profile is a crucial component of a QbD strategy and lays the groundwork for product development. In the context of New Drug Applications (NDAs), it is important to establish these targets early in the development phase, considering the drug substance's properties, product rationale and dosing frequency, as well as the target patient demographic. By planning with the end goal in mind, developers can create a resilient formulation and manufacturing process, supported by a solid control strategy that guarantees reproducible performance [19\u0026ndash;23].\u003c/p\u003e \u003cp\u003eCQAs are defined as properties\u0026mdash;whether physical, chemical, biological, or microbiological\u0026mdash;that must remain within specific limits to ensure the desired quality of the product. The selection of CQAs from the QTPP is influenced by the risk analysis. All quality attributes represent essential targets for the drug product and should be met through an effective quality management system, along with suitable formulation and process design to develop an effective control strategy. The current work deals with formulation development with major emphasis upon dissolution profile as the CQA [24\u0026ndash;25].\u003c/p\u003e \u003cp\u003eThe drug release investigation and release kinetics prediction showed a 24 h release profile as designed for once a daily dose. Apremilast CASD serves the dual purpose of solubility and bioavailability enhancement with reduced daily dose and side effects. The above characteristics increase dose tolerance of CASD to patients [21].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e1.2 Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs) :\u003c/h2\u003e \u003cp\u003eThe CMAs and CPPs evaluated in this study, along with their impact on dissolution and control strategies for Apremilast CASD are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. These high-risk ranking variables were further studied and optimized to define the design space. Within the design space, the changes of CPPs and CMAs are acceptable without compromising the product quality of CASD. Manufacturing of a CASD involves interplay of multiple factors with respect to materials as well as process parameters which in turn influence the product performance. The selection of dissolution parameters is essential to derive the correct dissolution outcome. The following section discusses development, dissolution, determination of dissolution kinetics and discriminatory power of selected dissolution for Apremilast CASD [26].\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDissolution Risk Assessment \u0026amp; Control strategy of Critical Variables\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eCritical Variable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEffect on Dissolution\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eControl Strategy\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDosage form type\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(Controlled release)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMatrix forms impact release profile and sensitivity to dissolution condition\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFor tablet dosage form USP-2 was selected and after dissolution development the same was finalized\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTablet shape\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSurface area and orientation in vessel influence wettability and hydrodynamic interaction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTablet shape was round and 8 mm round punch was finalized during product development\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRelease mechanism\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDiffusion, erosion, or osmotic systems demand tailored dissolution conditions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMethocel K100 LVCR has diffusion controlled followed by erosion. During formula optimization the optimum level also finalized.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAnalyst variability (Men/Analyst)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eManual handling, sampling, and interpretation can introduce inconsistency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTrain analysts thoroughly; use SOPs and automation where feasible\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDissolution parameters/conditions\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAgitation speed, medium pH, and volume influence hydrodynamics and drug release patterns\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOptimize and validate conditions for adequate discriminatory power for Apremilast CASD\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaterial \u0026amp; Process Attributes\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eRisk Assessment - Effect on Critical Quality Attributes (Dissolution)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eControl Strategy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eCritical Material Attributes\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eApremilast - Property\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eApremilast melting point (156.1℃) is very important for HME process and above melting points only active ingredient-polymer molecular level mixing is possible. Strong active ingredient-polymer interaction, especially molecular level interaction and bonding are helpful to improve stability of HME-ASD. So, the impact of melting point on dissolution is critical. The risk is high.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA processing temperature range of 40 to 160\u0026deg;C was maintained in the HME zones, exceeding the melting point of Apremilast, to promote molecular-level mixing beTween\u0026reg; the active ingredient and the polymer, thereby enabling full conversion to the amorphous state. The absence of particulate matter in the extrudates and the observation of a single-phase system confirmed uniform mixing at the molecular level.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eLevel of Solid dispersion polymer (Kollidone VA 64)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThe concentration of Kollidon VA 64 plays a critical role in stabilizing the solid dispersion of Apremilast. Without achieving the appropriate molecular-level interaction beTween\u0026reg; Apremilast and Kollidon VA 64 at the optimal ratio, complete conversion to the amorphous form\u0026mdash;and consequently, enhancement of solubility\u0026mdash;cannot be effectively attained.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1:2 ratio of Apremilast: Kollidone VA 64 was selected as the optimal formulation due to its superior solubility and stability in the Apremilast: Kollidone VA 64 solid dispersion. Alternative ratios demonstrated reduced solubility enhancement and exhibited the presence of particulate matter in the hot-melt extrudates, suggesting a lack of molecular-level mixing. Therefore, the 1:2 ratio was confirmed as the most effective\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eLevel Controlled release polymer (Methocel K100 LV CR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThe concentration of Methocel K100 LVCR plays a pivotal role in modulating the dissolution rate. Higher levels tend to slow down dissolution, whereas lower concentrations lead to an increased rate of dissolution\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMethocel K100LVCR concentration of 23.75% w/w was identified as optimal, achieving both a suitable dissolution rate and complete dissolution within 24 hours. Concentrations below this level led to a faster release but did not sustain dissolution, while higher concentrations resulted in a slower release and incomplete dissolution.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eCritical Process Parameters\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eHot Melt Extrusion Parameters\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eZone temperature has a pivotal role to ensure active ingredient-polymer miscibility at the molecular level and to ensure complete amorphous conversion. A process temperature above the melting point of active ingredient molecules ensures complete active ingredient miscibility and stable ASD. Based on the degree of active ingredient-polymer miscibility, amorphization, kinetic solubility and dissolution rate differs.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eProcessing temperature beTween\u0026reg; 40\u0026deg;C and 160\u0026deg;C was applied during the hot-melt extrusion process, surpassing the melting point of Apremilast to facilitate thorough interaction beTween\u0026reg; the drug and polymer at the molecular level. This approach ensured complete amorphization, as evidenced by the lack of visible particulates and the formation of a single-phase extrudate, indicating homogenous molecular mixing.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eTablet\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003ecompression\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eForce\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCompression force significantly influences tablet hardness that affects the rate and\u003c/p\u003e \u003cp\u003eextent of drug dissolution. As compression force increases hardness also increases,\u003c/p\u003e \u003cp\u003edissolution may slow due to reduced tablet disintegration, whereas decreased compression force results lower hardness often facilitates faster and more complete\u003c/p\u003e \u003cp\u003edissolution.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eApremilast CASD tablets with compression force up to 8\u0026ndash;10 tons results hardness\u003c/p\u003e \u003cp\u003ebeTween\u0026reg; 8 to 11 kP was found to provide an optimal balance, achieving both an\u003c/p\u003e \u003cp\u003eappropriate dissolution rate and complete drug release.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Materials\u003c/h2\u003e \u003cp\u003eApremilast was taken as a gift sample from M/s Hetero Labs, India. Kollidon\u0026reg; VA 64 from M/s BaSF, Triethyl citrate from M/s Vertellus, Klucel\u0026reg; LF from M/s Ashland, Methocel\u0026reg; K100 LVCR from M/s Dow, Colloidal silicon dioxide (Aerosil\u0026reg; 200) from M/s Evonik, microcrystalline cellulose from M/s FMC Biopolymer and Stearic Acid from M/s Nitika pharmaceuticals were obtained.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Methods\u003c/h2\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003e2.2.1 Development of Apremilast Amorphous Solid Dispersion\u003c/h2\u003e \u003cp\u003eDifferent ratios (1:1, 1:2, 1:3, 1:4) of Apremilast and Kollidon\u0026reg; VA 64 and HPMC-AS with 10.5% w/w Klucel\u0026trade; LF (hydroxypropylcellulose, low viscosity grade) combined to enhance film-forming and mechanical properties in dispersions, 0.9%w/w Aerosil\u0026reg; (colloidal silicon dioxide) as a \u003cem\u003eglidant\u003c/em\u003e and stabilizer to improve powder flow and prevent agglomeration and 3.67% w/w TEC (triethyl citrate) as \u003cem\u003eplasticizer\u003c/em\u003e that improves processability in HME and enhances flexibility of polymer matrices-were taken for hot melt extrusion. HME (Thermofisher Scientific, EuroLab 16 XL Twin-Screw Extruder, 100rpm, 40:1 L/D ratio XL 553\u0026ndash;5020) feeder (with feeder rpm from 2\u0026ndash;4) and torque 37\u0026ndash;42% maintaining ten zone temperature from 45\u0026deg; to 160\u0026deg;C (Zone 1\u0026ndash;35\u0026deg;C, Zone 2\u0026ndash;45\u0026deg;C, Zone 3\u0026ndash;95\u0026deg;C, Zone 4- 110\u0026deg;C, Zone5- 145\u0026deg;C, Zone 6-150\u0026deg;C, Zone 7-160\u0026deg;C, Zone 8-160\u0026deg;C, Zone 9-155\u0026deg;C, Zone 10\u0026ndash;35\u0026deg;C) [20]. The final extrudes were milled with a 0.5 mm screen in a co-mill (The SLS - Scalable Lab System, Quadro). The formulation trials have been added along with the supplementary information. Both extrudates were subjected to solubility evaluation across the physiological pH range [\u003cspan additionalcitationids=\"CR28 CR29\" citationid=\"CR26\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003ch2\u003e2.2.2 Solubility of Apremilast Amorphous Solid Dispersion\u003c/h2\u003e \u003cp\u003eAn excess amount of the Apremilast solid dispersion was added to a fixed volume of the chosen dissolution medium in a sealed container. The sealed mixtures were continuously stirred at a constant temperature, typically 37.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u0026deg;C, for 24 hours to ensure saturation. After equilibrium was attained, the suspension was filtered (using a 0.45 \u0026micro;m membrane filter) to separate the undissolved solid from the saturated solution. The concentration of Apremilast in the clear supernatant is quantified by HPLC.\u003c/p\u003e \u003cp\u003eDifferent ratios of Apremilast and Kollidon\u0026reg; VA 64 solid dispersion HME extrudes and Apremilast and HPMC-AS solid dispersion HME extrudes were taken for solubility study across physiological pH [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Solvents used were 0.1N HCl, 0.01N HCl, 0.001N HCl, water, pH 4.5 acetate buffer, pH 6.8 phosphate buffer, pH 7.2 phosphate buffer, pH 7.5 phosphate buffer.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003e2.2.3 Formulation Development of Apremilast CASD Tablets\u003c/h2\u003e \u003cp\u003eThe extrudes were milled with 0.5 mm screen in co-mill and mixed with Methocel\u0026reg; K100 LVCR, microcrystalline Cellulose and Aerosil\u0026reg; 200 after passing through ASTM #30 mesh (Bectochem) and blend for 10 minute in a double cone blender (SAAN Engineering) with 35% occupancy. Stearic acid was mixed into the blend and lubricated for 5 min in the same blender with 36% occupancy. The final lubricated blend was compressed into tablets in a compression machine (Cadmach, CMB-4-017).\u003c/p\u003e \u003cp\u003eA central composite design (CCD) was employed to evaluate the impact of critical material attributes on dissolution performance [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. The selected excipients\u0026mdash;Kollidon\u0026reg; VA 64, Klucel\u0026trade; LF, Triethyl Citrate (TEC), and Hypromellose (Methocel\u0026trade; K100 LVCR)\u0026mdash;were investigated as independent variables, with dissolution profiles at 2, 6, and 24 hours serving as response parameters (Supplementary Information).\u003c/p\u003e \u003cp\u003eDissolution is a critical quality attribute (CQA) because it directly influences drug release and bioavailability, especially in oral solid dosage forms. Ishikawa diagram correctly describes the variables involved for dissolution of final dosage form (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) [32\u0026ndash;38].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe selection of dissolution parameters like, surfactant concentration, agitation, media volume, pH, apparatus are very important in order to finalize the discriminatory dissolution condition [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. The risk assessment and control strategy for variables affecting dissolution are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e elaborates how key CMAs and CPPs influence dissolution, and outlines control strategies to ensure batch-to-batch consistency and robust product performance.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003e2.2.4 Discriminatory Dissolution Method Development of Apremilast CASD Tablets\u003c/h2\u003e \u003cp\u003eThe dissolution method for the prototype formulation is chosen to ensure the best suitable rate and extent of dissolution [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. This selection process involves manipulating different parameters such as the volume of the dissolution media, agitation speed, type of apparatus (either paddle or basket), and the pH of the media. Media pH was chosen based on highest solubility of amorphous solid dispersion so that sink conditions can be maintained during dissolution. Dissolution apparatus was chosen based on the comparative dissolution profile between USP-1 and USP 2. The choice between the two apparatus depends on the dosage form, its release characteristics, and regulatory guidelines to ensure accurate dissolution testing, supporting bioavailability and therapeutic efficacy [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e42\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section4\"\u003e \u003ch2\u003e2.2.4.1 Selection of Surfactant Concentration\u003c/h2\u003e \u003cp\u003eInitially, as per practice, USP apparatus II was chosen for tablet dosage form to assess the effect of surfactant concentration. From the solubility graph, the maximum solubility was observed in pH 4.5 Acetate buffer. Further the dissolution study was conducted in pH 4.5 acetate buffer with media volume 900 ml and paddle speed 75 rpm for initial evaluation by varying surfactant, Tween\u0026reg;80 concentration from 0 to 2% [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e43\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section4\"\u003e \u003ch2\u003e2.2.4.2 Selection of Agitation Speed\u003c/h2\u003e \u003cp\u003eAgitation speed in dissolution testing directly influences the hydrodynamics of the dissolution medium, affecting the drug release rate and dissolution behaviour. Higher agitation speeds create greater turbulence, enhancing the convective flow around the dosage form and improving drug diffusion from its surface into the surrounding medium. This can accelerate the dissolution process, especially for poorly soluble drugs [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. However, excessive agitation can introduce higher shear forces, potentially altering the physical structure of sensitive formulations, such as soft capsules or extended-release tablets, leading to deviations in the intended release profile. Conversely, slower agitation speeds reduce turbulence, providing a gentler dissolution environment that may be preferable for formulations requiring controlled or slow release. Thus, the optimal agitation speed must balance efficient drug release with the preservation of the dosage form\u0026rsquo;s integrity, ensuring accurate and reproducible dissolution testing. 50, 75, 100 rpm were chosen to access the dissolution behaviour. [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e45\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section4\"\u003e \u003ch2\u003e2.2.4.3 Selection of Dissolution Apparatus\u003c/h2\u003e \u003cp\u003eEffect of dissolution apparatus was also evaluated keeping other dissolution parameters same like 1% w/w Tween\u0026reg;80 in 50 mM Sodium Acetate Buffer pH 4.5, 900 ml, 75 rpm [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e46\u003c/span\u003e]\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section4\"\u003e \u003ch2\u003e2.2.4.4 Selection of Media Volume\u003c/h2\u003e \u003cp\u003eFor poorly soluble drugs, maintaining sink conditions\u0026mdash;where the volume of dissolution medium should be large enough to prevent the drug concentration from exceeding its solubility\u0026mdash;is critical for accurate dissolution testing. Appropriate media volume ensures that the drug remains in a supersaturated state, promoting continuous dissolution. Ensuring an appropriate volume helps to simulate realistic gastrointestinal conditions and provides reliable data for poorly soluble drugs [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. The effect of media volume on dissolution of Apremilast CASD was evaluated as mentioned below Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section4\"\u003e \u003ch2\u003e2.2.4.5 Selection of Media pH\u003c/h2\u003e \u003cp\u003eFrom the solubility data highest solubility was achieved in pH 4.5 acetate buffer. So initially pH 4.5 acetate buffer was selected for dissolution development. Additionally, in other pH the dissolution behaviour was examined keeping optimised dissolution parameter 1% w/w Tween\u0026reg;80 in, 900 ml, 75 rpm USP II Apparatus (Paddle) [\u003cspan additionalcitationids=\"CR49 CR50 CR51 CR52 CR53\" citationid=\"CR47\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e54\u003c/span\u003e]\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e \u003ch2\u003e2.2.5 Design of Experiments\u003c/h2\u003e \u003cp\u003eThe media pH 4.5 was selected based on the highest solubility of Apremilast CASD and USP II was chosen based on its suitability for tablet dosage form and more uniform release observed compared to USP I. The design of experiments was performed using three critical variables. The experimental design and response specifications are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e56\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDesign Summary\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFactors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRuns\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReplicates\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCenter pts (total)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTool\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eMinitab\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVariables\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e\u003cb\u003eResponses\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFactors\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eLower Limit\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eHigher Limit\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eResponses\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eSpecification\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVolume of Media (ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e800\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e%Dissolution at 2h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10\u0026ndash;35%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAgitation Speed (rpm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e%Dissolution at 6 h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e40\u0026ndash;60%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurfactant Level (% w/w)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e%Dissolution at 24 h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNLT 80%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section3\"\u003e \u003ch2\u003e2.2.6 Setting Dissolution Specification-Apremilast CASD Tablets\u003c/h2\u003e \u003cp\u003eAs per USP\u0026thinsp;\u0026lt;\u0026thinsp;1092\u0026gt; [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e49\u003c/span\u003e] and CDER [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e41\u003c/span\u003e] and EMA guidance [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e51\u003c/span\u003e] on modified release products, minimum three time points should be included in the specification for controlled release formulation- A loading or initial point (typically 20\u0026ndash;30% release), intermediate point (around 50% release) and final time point (at least 80% release). The same was adopted in the present study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section3\"\u003e \u003ch2\u003e2.2.7 Dissolution Kinetics\u003c/h2\u003e \u003cp\u003eThe dissolution profile of the formulation was analysed using several model-dependent release kinetics approaches, including zero-order, first-order, Higuchi, Hixson\u0026ndash;Crowell, and Korsmeyer\u0026ndash;Peppas models [\u003cspan additionalcitationids=\"CR53\" citationid=\"CR51\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. These models were applied to the experimental data to determine the most suitable mechanism of drug release.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section3\"\u003e \u003ch2\u003e2.2.8 Discriminatory Power of Selected Dissolution\u003c/h2\u003e \u003cp\u003eThe discriminatory capability of the dissolution method refers to its ability to identify changes in the drug product. Proving the method\u0026rsquo;s discriminatory power is both challenging and essential, especially when monitoring active pharmaceutical ingredient (API) or formulation factors that are crucial for the optimal performance of poorly soluble compounds. In an ideal scenario, the dissolution test conditions should be sensitive enough to detect changes in the product that could impact its biopharmaceutical performance [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. The ability of a dissolution method to discriminate is crucial in determining whether it can detect changes in critical material attributes (CMAs) and critical process parameters (CPPs) that might influence the drug's bioavailability [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e58\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe selected dissolution media was tested for the discriminatory potential by changing the polymer concentration.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eThe physical characterization of Apremilast CASD has been included in the supplementary information.\u003c/p\u003e\n\u003cdiv id=\"Sec21\"\u003e\n \u003ch2\u003e3.1 Solubility of Apremilast Solid Dispersion\u003c/h2\u003e\n \u003cp\u003eThe solubility of Apremilast solid dispersion prepared with different Apremilast: Kollidon VA 64 ratios across physiological pH conditions is shown in Fig.\u0026nbsp;2. The study revealed (Fig.\u0026nbsp;2) that the solid dispersion of Apremilast with Kollidon VA 64 at a 1:2 ratio exhibited the highest solubility across all tested pH conditions, outperforming other ratios as well as formulations with HPMC-AS. Consequently, the API\u0026ndash;Kollidon VA 64 (1:2) solid dispersion was selected for further development [59\u0026ndash;60].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec22\"\u003e\n \u003ch2\u003e3.2 Dissolution of Apremilast CASD tablets\u003c/h2\u003e\n \u003cp\u003eTablets with Hypromellose (Methocel K100 LVCR) at 20% w/w produced a faster release rate of Apremilast compared with 23.75% w/w, whereas increasing the level to 27.5% w/w led to a slower release and incomplete drug release over 24 hours. Tablets Methocel K4M at 3.75% and 6.25% w/w, as well as Methocel K100M at 2.5% and 5% w/w, also exhibited slower release rates with incomplete release up to 24 hours. Similarly, the hydrophobic polymer ethyl cellulose (7 cps) at 2.5% and 5% w/w resulted in incomplete drug release. Polymer concentrations below 2.5% w/w were found to be difficult to uniformly disperse within the blend, potentially leading to dissolution variability. Among all formulations evaluated, Methocel K100 LVCR at 23.75% w/w demonstrated the most optimal controlled-release profile over a 24-hour period (Supplementary information)\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec23\"\u003e\n \u003ch2\u003e3.4 Discriminatory Dissolution Development\u003c/h2\u003e\n \u003cdiv id=\"Sec24\"\u003e\n \u003ch2\u003e3.4.1 Surfactant Concentration\u003c/h2\u003e\n \u003cp\u003eThe effect of surfactant concentration on the dissolution behavior of Apremilast CASD indicated that 1% w/w Tween\u0026reg; 80 provided optimal dissolution performance (Fig.\u0026nbsp;3.). Lower concentrations led to incomplete release, while higher concentrations increased variability. These findings are consistent with the literature [61\u0026ndash;62].\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec25\"\u003e\n \u003ch2\u003e3.4.2 Agitation Speed\u003c/h2\u003e\n \u003cp\u003eAgitation speed pf 75 rpm yielded complete release with low % RSD, outperforming 50 rpm (slow, variable) and 100 rpm (fast, variable) [63\u0026ndash;64] as illustrated in Fig.\u0026nbsp;3.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec26\"\u003e\n \u003ch2\u003e3.4.3 Dissolution Apparatus\u003c/h2\u003e\n \u003cp\u003eUSP Apparatus II (paddle) showed uniform and complete drug release compared to USP Apparatus I (basket) [65\u0026ndash;66] as illustrated in Fig.\u0026nbsp;3.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec27\"\u003e\n \u003ch2\u003e3.4.4 Media Volume\u003c/h2\u003e\n \u003cp\u003eThe effect of dissolution media volume on the release of Apremilast CASD is illustrated in Fig.\u0026nbsp;3.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec28\"\u003e\n \u003ch2\u003e3.4.5 Media pH\u003c/h2\u003e\n \u003cp\u003eThe effects of media pH, surfactant concentration, agitation speed, dissolution apparatus, media volume, on the dissolution behavior of Apremilast CASD are illustrated in Fig.\u0026nbsp;3. pH 4.5 acetate buffer confirmed optimal drug release with low variability.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec29\"\u003e\n \u003ch2\u003e3.5 Design of Experiments\u003c/h2\u003e\n \u003cp\u003eFor dissolution at 2 h and 6h, all main variable and interaction effects were significant (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Whereas, for dissolution at 24 h, agitation and surfactant level were significant however volume of media and interaction of volume and agitation speed was not significant within the studied range [46\u0026ndash;47].\u003c/p\u003e\n \u003cp\u003eStatistical analysis (supplementary information) confirmed significance of media volume, agitation, and surfactant level at 2 h and 6 h (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). At 24 h, agitation and surfactant remained significant, while media volume and its interaction with agitation were found to be insignificant [55\u0026ndash;56].\u003c/p\u003e\n \u003cp\u003eThe influence of critical dissolution variables and the defined design space are depicted through contour plots is shown in Fig.\u0026nbsp;4.\u003c/p\u003e\n \u003cp\u003eThe impact of main effect plots, design space 2 h (10\u0026ndash;35%), 6 h (40\u0026ndash;60%), 24 h (\u0026ge;\u0026thinsp;80%) have been included in the supplementary information.\u003c/p\u003e\n \u003cp\u003eFrom the main effect graph, at 2h and 6 h,all main effects (media volume, agitation and surfactant level) have a positive effect on dissolution, if the main effect level increases the dissolution will also increase [62]. At 24 h, agitation and surfactant level have strong positive effect whereas media volume has very slight positive effect. From the contour plot, the design space can be selected based on specification criteria of % dissolution at 2h should be 10\u0026ndash;35%; at 6 h should be 40\u0026ndash;60% and at 24 h should be NLT 80%.\u003c/p\u003e\n \u003cp\u003eFinally, 1% w/w Tween\u0026reg; 80 in 900 ml pH 4.5 acetate buffer, agitation speed of 75 rpm, USP 2 apparatus were selected for dissolution of Apremilast CASD.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec30\"\u003e\n \u003ch2\u003e3.6 Dissolution Specification \u0026ndash; Apremilast CASD\u003c/h2\u003e\n \u003cp\u003eSpecifications were finalized (Table\u0026nbsp;2) based on optimized parameters and regulatory guidance [49\u0026ndash;50]. The finalized dissolution specifications for Apremilast CASD tablets complied with the decided specifications. Tabular representation of the same can be found in the supplementary information.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec31\"\u003e\n \u003ch2\u003e3.7 Dissolution Kinetics\u003c/h2\u003e\n \u003cp\u003eThe Hixson\u0026ndash;Crowell model proved to be the best fit (R\u0026sup2; = 0.9969) for the dissolution profile, as shown in Fig.\u0026nbsp;5, indicating erosion-controlled drug release [52\u0026ndash;54 and 67\u0026ndash;70].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec32\"\u003e\n \u003ch2\u003e3.8 Discriminatory Power\u003c/h2\u003e\n \u003cp\u003eThe selected medium effectively discriminated against formulation variables such as polymer concentration and process variations like hardness. Tablet hardness and Methocel\u0026reg; K100 LVCR concentration critically influenced dissolution. The discriminatory nature of the selected dissolution method under varying formulation and process conditions is tabulated in Table 3.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTable 3: Discriminatory nature of selected dissolution media for Apremilast CASD\u003c/strong\u003e\u003c/p\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"594\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 594px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiscriminatory nature of selected dissolution media\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 43px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTime (h)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSpecification Limit\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 455px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1 % w/w Tween\u0026reg; 80 in 50 mM Sodium Acetate Buffer pH 4.5, 900 ml, USP-2, 75 rpm\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOptimum Formulation (hardness 8-11 kp)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 172px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLowering level (-20 % w/w) Methocel K100 LVCR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLow Hardness (5-7 kp)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAvg\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(min - max)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e% RSD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 172px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAvg\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;(min - max)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e% RSD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 131px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAvg\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(min - max)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e% RSD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 43px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 152px;\"\u003e\n \u003cp\u003e7 \u0026plusmn; 8.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 172px;\"\u003e\n \u003cp\u003e3 \u0026plusmn; 75.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 131px;\"\u003e\n \u003cp\u003e19 \u0026plusmn; 17.68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 43px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e10 - 35\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 152px;\"\u003e\n \u003cp\u003e22 \u0026plusmn; 5.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 172px;\"\u003e\n \u003cp\u003e7 \u0026plusmn; 24.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 131px;\"\u003e\n \u003cp\u003e33 \u0026plusmn; 10.52\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 43px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 152px;\"\u003e\n \u003cp\u003e35 \u0026plusmn; 3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 172px;\"\u003e\n \u003cp\u003e18 \u0026plusmn; 19.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 131px;\"\u003e\n \u003cp\u003e47 \u0026plusmn; 7.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 43px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e40 - 60\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 152px;\"\u003e\n \u003cp\u003e45 \u0026plusmn; 2.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 172px;\"\u003e\n \u003cp\u003e31 \u0026plusmn; 6.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 131px;\"\u003e\n \u003cp\u003e61 \u0026plusmn; 4.08\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 43px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 152px;\"\u003e\n \u003cp\u003e62 \u0026plusmn; 6.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 172px;\"\u003e\n \u003cp\u003e53 \u0026plusmn; 3.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 131px;\"\u003e\n \u003cp\u003e77 \u0026plusmn; 5.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 43px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e12\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 152px;\"\u003e\n \u003cp\u003e77 \u0026plusmn; 7.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 172px;\"\u003e\n \u003cp\u003e65 \u0026plusmn; 3.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 131px;\"\u003e\n \u003cp\u003e84 \u0026plusmn; 2.85\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 43px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e16\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 152px;\"\u003e\n \u003cp\u003e88 \u0026plusmn; 2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 172px;\"\u003e\n \u003cp\u003e76 \u0026plusmn; 3.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 131px;\"\u003e\n \u003cp\u003e92 \u0026plusmn; 2.48\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 43px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e24\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNLT 80\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 152px;\"\u003e\n \u003cp\u003e98 \u0026plusmn; 2.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 172px;\"\u003e\n \u003cp\u003e88 \u0026plusmn; 4.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 131px;\"\u003e\n \u003cp\u003e99 \u0026plusmn; 2.41\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThe development of a discriminatory dissolution method for Apremilast CASD was achieved by QbD framework, ensuring systematic optimization of formulation and process variables. Solubility profiling across physiological pH confirmed that Apremilast: Kollidon\u0026reg; VA 64 (1:2) extrudes exhibited highest solubility in pH 4.5 acetate buffer, justifying its selection for dissolution media to maintain sink conditions and ensure consistent release.\u003c/p\u003e \u003cp\u003eSurfactant concentration emerged as a critical variable, with 1% Tween\u0026reg; 80 delivering optimal dissolution performance\u0026mdash;balancing release rate and minimizing % RSD. Lower concentrations led to incomplete release, while higher levels introduced variability [\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e71\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e72\u003c/span\u003e]. Agitation speed was equally influential; 75 rpm provided complete release with low variability, outperforming both slower (50 rpm) and faster (100 rpm) conditions [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e64\u003c/span\u003e]. Among apparatus types, USP-II (paddle) demonstrated superior performance over USP-I (basket), offering uniform and complete release profiles aligned with regulatory expectations for tablet dosage forms [\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e73\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e74\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMedia volume was another determinant of robustness of the discriminatory dissolution medium. A volume of 900 ml ensured sink conditions and minimized variability, supporting reproducible performance. DoE approach validated the statistical significance of surfactant level, agitation speed, and media volume\u0026mdash;particularly at early time points (2 h and 6 h), while at 24 h, agitation and surfactant remained dominant influencers. Contour plots and main effect helped define a design space that supports regulatory flexibility and batch-to-batch consistency [\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e75\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eKinetic modeling revealed that the Hixson\u0026ndash;Crowell model best described the release mechanism (R\u0026sup2; = 0.9969), indicating erosion-controlled dissolution with uniform tablet size reduction. This aligns with the intended controlled-release profile of Apremilast CASD, designed for once a day dosing and reduced cumulative dose [\u003cspan additionalcitationids=\"CR77\" citationid=\"CR75\" class=\"CitationRef\"\u003e76\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e78\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe discriminatory power of the selected method was evaluated by altering critical material attributes (e.g., Methocel\u0026reg;K100 LVCR concentration) and process parameters (e.g., tablet hardness). Increased levels of Methocel\u0026reg; led to slower release and failure to meet dissolution specifications at 1 h and 6 h, confirming the method\u0026rsquo;s sensitivity to formulation changes. This validates its utility in routine quality control and formulation development, ensuring robust performance and regulatory compliance [\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e79\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e80\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn summary, the optimized dissolution method\u0026mdash;1% Tween\u0026reg; 80 in 900 ml pH 4.5 acetate buffer at 75 rpm using USP-II\u0026mdash;demonstrated reproducibility, sensitivity, and alignment with controlled-release kinetics.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eApremilast CASD was successfully developed by HME using DoE. The dissolution method for Apremilast, was optimized with respect to media volume, agitation, pH, and apparatus to provide a discriminatory dissolution medium. Controlled-release kinetics aligned with the Hixson\u0026ndash;Crowell model, ensuring uniform tablet erosion. Experimental design statistically validated the discriminating power of the medium across formulations. A QbD-DoE enabled discriminatory dissolution medium provides an adequate platform to gauge the qualitative as well quantitative impact exerted by the process these variables, involved in formulation of a CASD thereby allowing a sustainable and robust formulation development.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eQbD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eQuality by Design\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eQTPP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eQuality Target Product Profile\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCQA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCritical Quality Attribute\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCASD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eControlled-Release Amorphous Solid Dispersion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eASD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAmorphous Solid Dispersion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHME\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHot-Melt Extrusion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDOE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDesign of Experiments\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCMA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCritical Material Attribute\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCPP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCritical Process Parameter\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eOFAT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eOne Factor At a Time\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFDA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFood and Drug Administration\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCDER\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCenter for Drug Evaluation and Research\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eEMEA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eEuropean Medicines Agency (now formally EMA)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRelative Standard Deviation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors are grateful for the gift sample of Apremilast from M/s Hetero Labs. We would like to acknowledge Department of Science and Technology (SR/FST/College-054/2017) for the infrastructure.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCredit: Sandipan Roy: Formal analysis, Investigation, Writing;\u003c/p\u003e\n\u003cp\u003eApoorva Phadke- Conceptualization, writing, review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003eNehal Sarvaiya – Review and editing\u003c/p\u003e\n\u003cp\u003eSujata Sawarkar \u0026amp; Vaishali Y. Londhe: Conceptualization, Supervision, Writing – review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;Statements and Declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe authors declare no conflict of interest.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;Funding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author(s) reported there is no funding associated with the work featured in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that all the supporting data are con­tained within the paper.\u003cbr\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;Future Scope: PK-PD studies with IVIVC correlation\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLee MR, Hsieh KS, Gage WB, Tillman AJ, Carlin JS. 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Int J Pharm. 2012;424:154\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Controlled Amorphous Release Solid Dispersion (CASD), Quality by Design (QbD), Once A Day Dosing, Dissolution Development, Design of Experiment (DoE), Discriminatory Dissolution Medium","lastPublishedDoi":"10.21203/rs.3.rs-8916904/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8916904/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eThe study was aimed to formulate a novel once a day Controlled Release Amorphous Solid Dispersion (CASD) and design a discriminatory dissolution method for analysis of the release behaviour.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eApremilast and Kollidon\u0026reg; VA 64 (1:2) were formulated into an amorphous solid dispersion by QbD enabled hot melt extrusion (HME). The extrudates were mixed with high-viscosity Hypromellose, colloidal silicon dioxide as glidant, and stearic acid as lubricant to form tablets. Initial dissolution parameters were determined using the One Factor at A Time (OFAT) method, later refined through Design of Experiment (DoE) approach with three variables\u0026mdash;agitation speed, media volume, and surfactant concentration that validate the dissolution method, resulting in a curated design space based on the defined specifications. The discriminatory capacity of the finalized dissolution media was evaluated by altering critical quality attributes (CQAs) like polymer concentration and critical process parameters (CPP) like tablet hardness.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eDissolution parameters such as pH (4.5), surfactant concentration (1%w/w Tween\u0026reg; 80), volume (900mL), agitation speed (75rpm), and apparatus (type II) were found to significantly influence method development, enabling the detection of minor variations in formulation attributes and manufacturing process parameters.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis QbD-DoE based study of formulation development and design of discriminatory dissolution of Apremilast CASD offers a novel once a day substitute to the traditional high dose multi-frequency regime with an effective discriminatory dissolution medium ensuring reliable product performance against subtle formulation differences. showcases successful application of QbD based development approach. The selected dissolution method effectively discriminates against subtle formulation differences, ensuring reliable product performance.\u003c/p\u003e\u003ch2\u003eGraphical Abstract\u003c/h2\u003e \u003cp\u003e \u003c/p\u003e","manuscriptTitle":"Formulation Development and Design of Discriminatory Dissolution Medium for Controlled Release Amorphous Solid Dispersion of Apremilast for Once A Day Administration: A QbD Approach","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-29 19:49:56","doi":"10.21203/rs.3.rs-8916904/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"975722f6-4b15-41af-9860-713ebce4bc74","owner":[],"postedDate":"April 29th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-29T19:49:56+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-29 19:49:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8916904","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8916904","identity":"rs-8916904","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}