{"paper_id":"4bee32fe-2ef1-44d5-a9a6-7830adbda391","body_text":"1 RESEARCH ARTICLE\n2 Title: An Alternative Approach to Tablet Splitting and Grinding for Medication Administration\n3\n4 Rajneesh Taneja1, Joseph Scarim2, Poonam G Pande1*, Anthony Scarim2, Milap C Nahata3, Rita K \n5 Jew4, Koteswara Inabathina1\n6\n7 1Global Alliance for TB Drug Development (TB Alliance); 2JSAS Services Inc; 3Institute of \n8 Therapeutic Innovations and Outcomes, Colleges of Pharmacy and Medicine, The Ohio State \n9 University; 4Institute for Safe Medication Practices (ISMP)\n10\n11 *Correspondence\n12 Poonam Pande, TB Alliance, 40 Wall Street, 24th Floor, New York, NY 10005\n13 e-mail: poonam.pande-consultant@tballiance.org\n14\n15 Running head: Alternative method for suspending oral tablets\n16\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.\n\n17 Abstract\n18 Purpose. Tablet formulations fail to meet the needs of patients unable to swallow tablets such \n19 as pediatric, elderly, and patients that must receive medications via feeding tubes. Our aim was \n20 to develop and test a new, simple device (XTEMP-RTM) and the methodology for converting \n21 tablets into a homogeneous suspension for medication administration.\n22 Methods. We developed a new device comprised of a flexible receptacle, a tight-fitting cap, and \n23 a suction cup bottom to convert tablets into liquid preparations. TB treatment drugs, TBAJ-876 \n24 and TBI-223, were dispersed within the device utilizing water and commonly available \n25 suspending vehicles. We investigated the effectiveness of the XTEMP-R device in dispersing \n26 tablets. This was accomplished by visual observations, determining the fineness of dispersion, \n27 and measuring the total drug recovery from the dispersions in XTEMP-R. We investigated the \n28 accuracy and reproducibility of delivering aliquots from these suspensions by determining the \n29 dose reproducibility upon suspension and upon redispersion after 24 hours. The effectiveness \n30 of the device was also evaluated using commercially available tablets of acetaminophen, \n31 amlodipine, glimepiride, metformin and valsartan.\n32 Results. The suspensions were visually uniform without any large particles. The suspensions \n33 passed through #18 sieve confirming that the particles were less than 1000 µm. Average total \n34 dose recovery of three suspensions each was determined to be 101.3% and 99.2% for TBI-223 \n35 and TBAJ-876, respectively. Reproducibility from aliquots of 2 mL each were 98.9-99.7% for \n36 three replicates of TBI-223 suspensions, and 102.6-103.2% for TBAJ-876 suspensions. Aliquots \n37 tested after 24 hours confirmed uniform re-dispersibility.\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n38 Conclusion. We have demonstrated that XTEMP-R can be utilized to prepare homogeneous \n39 suspensions can be prepared conveniently and efficiently in less than 10 minutes without any \n40 drug loss. Aliquots for partial dose delivery can be withdrawn accurately. These findings \n41 demonstrate that XTEMP-R can be used to accurately deliver doses of suspensions for patients \n42 who cannot swallow tablets.\n43\n44 Keywords: aliquot, device, dosing, dysphagia, geriatric, pediatric, suspension\n45\n46\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n47 Introduction\n48 Tablets remain the most common modality for oral dose administration of drugs. They \n49 represent 28 of the top 30 prescription drugs in 2021 [1]. However, these formulations are not \n50 suitable for some patients, especially young children, and those suffering from dysphagia. \n51 Tablet administration is also a challenge for patients receiving enteral tube feeding [2]. If an \n52 alternate oral formulation or route of administration is unavailable, manipulation of the dosage \n53 form may be undertaken at the point of administration to provide the prescribed dose [3]. \n54 Manipulation involves physical alteration of the dosage form, including tablet splitting, \n55 crushing, or grinding [4]. Dose adjustment is commonly achieved through tablet splitting, \n56 whereas tablet crushing or grinding aid the swallowing or administration via an enteral feeding \n57 tube [4].\n58 Tablets are often pulverized (crushed or ground) with a mortar and pestle or other tablet \n59 grinding device to facilitate administration [2,5]. However, this process is tedious and often \n60 leads to the loss of the prescribed dose during preparation or administration [5]. In one study, it \n61 was demonstrated that two rinses of the grinding devices with water were required to prevent \n62 significant drug loss [5]. Screwcap crushers yield larger particles that are not suited for feeding \n63 tube administration [4]. Also, some hazardous drugs may pose risks to caregivers preparing the \n64 doses through the inhalation of generated powder containing the drug, or through contact with \n65 skin, nose, and eyes [4]. \n66 Another common practice is tablet splitting [6,7]. It is used for many reasons including \n67 delivering partial dose of the tablet, facilitating swallowing, or cost savings [8,9]. However, this \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n68 process raises the issues of drug loss, variation in dose uniformity, dose accuracy, and weight \n69 uniformity between fragments [8]. Many tablets may not be suitable for splitting due to factors \n70 such as hardness, size, shape, or absence of score line.\n71 Steadman and colleagues [5] called for a device that minimizes drug loss and maximizes \n72 medication delivery, i.e., a device that ensures a sealed environment for crushing followed by \n73 mixing with a fluid and subsequent consumption from the same receptacle [5]. Salmon and \n74 colleagues [2] expressed a need for a combined crushing and suspending device.\n75 TBAJ-876 (US IND number 145,349) and TBI-223 (US IND Number 134,334) are two new \n76 chemical entities under development as immediate-release tablets for the treatment of \n77 tuberculosis. The tablets are available in 100 mg and 600 mg strengths, respectively. Dose \n78 titration is required while conducting early clinical studies with these drugs. A liquid \n79 formulation allows for the flexibility of aliquoting the desired dose in any fraction. The \n80 alternative is to manufacture tablets in multiple strengths and choose a combination of \n81 different strength tablets for the desired dose.\n82 The objective of our work was to develop a device and methodology that enabled the \n83 dispersion of TBI-223 and TBAJ-876 immediate-release tablets into a suspension in water \n84 without the need for crushing or grinding in a contained environment. Further, a suspending \n85 vehicle can be added to make it into a homogenous suspension that allows for accurate partial \n86 dose delivery.\n87 A new, simple device (XTEMP-RTM) was developed, and the methodology for converting tablets \n88 into a homogeneous suspension with this device is described in this paper. This device and \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n89 methodology can be used in any setting without crushing, grinding, or splitting the tablet \n90 dosage form. Flavors and sweeteners may be added to the suspension for enhancing \n91 palatability. Our work is not suited for modified release, delayed-release, or controlled-release \n92 tablets and capsules. In this paper, the term tablet refers to immediate-release tablet. The term \n93 dispersion refers to the disintegration of the tablet in a liquid media resulting in a suspension. \n94 The terms dispersion and suspension convey the same meaning.\n95 To demonstrate the utility of the XTEMP-R device, we investigated (a) time to disperse the \n96 tablets, (b) fineness of dispersion, (c) total dose recovery, and (d) accuracy of delivering aliquots \n97 from suspensions.\n98 In addition to TBAJ-876 and TBI-223, the dispersibility of a few commercial tablets was also \n99 conducted to verify the utility of this device.\n100 Materials and methods\n101 Drugs and vehicles\n102 TBI-223 IR tablets, 600 mg, TB Alliance, lot 6767AU01, retest 11/2022\n103 TBAJ-876 Tablets, 100 mg, TB Alliance, Batch 6767BG01, retest 10/2022\n104 Valsartan tablets, USP, 320 mg (Macleods, lot EVI2032A, exp 07/2022)\n105 Tylenol® (acetaminophen) extra-strength tablets, 500 mg (Johnson & Johnson, lot AFA111, exp \n106 05/2025)\n107 Metformin tablets, USP, 1000 mg (Ascend, lot 4200094A, exp 07/2023)\n108 Glimepiride tablets, USP, 2 mg (Accord, lot P2005847, exp 10/2023)\n109 Amlodipine tablets, USP, 2.5 mg, (Ascend, lot 21140696, exp 01/2024)\n110 ORA-Blend®, Perrigo, lot 2077398, exp. 28 Feb 2025\n111 ORA-Sweet®, Perrigo, lot 1346049, exp 31 July 2024\n112 Water, Distilled, Culligan, R22075 06:56 L1 Best By 03/2023\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n113\n114 Chemicals\n115 Acetonitrile, HPLC, Spectrum Chemical Mfg. Corp, item HP412, lot 20020323\n116 Water, HPLC, Concord Technology, 8003LC4000, lot 201222\n117 Ammonium Acetate, Sigma-Aldrich, item 73594-25G-F, lot BCCH0197\n118 Trifluoroacetic acid (TFA), HPLC grade, Sigma-Aldrich, item 91707-10X1ML, lot bccg6537\n119 Sodium lauryl sulfate (SLS), Sigma-Aldrich, Reagent grade, item 436143, lot MKCQ6608\n120\n121 Equipment and supplies\n122 HPLC: Hitachi L-2100 pump, Shimadzu SPD-10AVP detector, Shimadzu SCL-10AVP controller, \n123 Shimadzu CTO-AVP column heater, SRI Instruments PeakSimple chromatography data system\n124 Column: Zorbax Bonus RP (C18, 4.6 mm x 150 mm, 3.5μm)\n125 Column: Waters Symmetry Shield RP-8 (4.6 mm x 150 mm, 5μm)\n126 Syringe Filters, Tisch Scientific, Glass Fiber, Hydrophilic, 25mm, 1.0um, PN SF14699, lot \n127 170420083\n128 Syringe Filters, PALL Life Sciences, PVDF, 13mm, 0.45um, PN 4545, lot A10648946\n129\n130 XTEMP-RTM device\n131 XTEMP-R comprises a flexible receptacle, a tight-fitting cap, and a suction cup bottom (Fig 1). It \n132 is a soft walled device manufactured with biocompatible, low hardness HCR (high-consistency \n133 silicone rubber) sourced from Wacker, Germany. The construction material, platinum-cured \n134 silicone, complies with FDA 21 CFR 177.2600, German Bfr XV, France Arrete Du 25, ROHS, \n135 TSE/BSE free, USP Class VI Certification, and ISO 10993 Certification. These devices are \n136 produced by a compression molding process (Ami Polymers Pvt. Ltd., India) in a class 10000 \n137 cleanroom. The height of the XTEMP-R device is 140 mm, the internal diameter is 22 mm, and \n138 the capacity is approximately 40 mL. The device has volume markings on the outside at 5-mL \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n139 intervals starting at 15 mL. This device is resistant to extremes of environments and \n140 temperatures and is designed to be leak-resistant and is easy to squeeze between the fingers \n141 for manual dispersion of the tablets. \n142 Fig 1. X-TEMP-RTM Device.\n143\n144 Preparation of suspensions from tablets using XTEMP-R\n145 The general preparation technique is displayed in Fig 2 with preparation of TBI-223 suspension \n146 as an example.\n147 Fig 2. Preparation of TBI-223 Suspension from Tablets.\n148\n149 TBAJ-876\n150 One tablet of TBAJ-876 100 mg was added to the XTEMP-R followed by 5 mL of water. The \n151 device was capped and swirled for 5 seconds and left undisturbed for 5 minutes. Then the \n152 tablet was manually massaged in the XTEMP-R for 2 minutes. ORA-Sweet suspending vehicle, \n153 19.5 mL was added to the dispersion in the XTEMP-R make a final volume that coincided with \n154 the 25-mL mark on the device and a final concentration of 4 mg/mL. The device was capped \n155 and shaken 25 times to mix thoroughly. For redispersion, the suspension was shaken 25 times.\n156 TBI-223\n157 One tablet of TBI-223 600 mg was added to the XTEMP-R followed by 5 mL of water. The device \n158 was capped and swirled for 5 seconds and left undisturbed for 5 minutes. Then the tablet was \n159 manually massaged in the XTEMP-R for 2 minutes. ORA-Blend suspending vehicle, 9.4 mL was \n160 added to the dispersion in the XTEMP-R to make a final volume that coincided with the 15-mL \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n161 mark on the device and a final concentration of 40 mg/mL. The device was capped and shaken \n162 25 times to mix thoroughly. For redispersion, the suspension was shaken 25 times.\n163 Evaluation of suspensions prepared in XTEMP-R\n164 Visual observation\n165 TBAJ-876 and TBI-223\n166 The prepared suspensions of TBAJ-876 and of TBI-223 were shaken, and then an aliquot of each \n167 was poured onto a watch glass. The suspensions were examined for color, uniformity, and \n168 presence of large particles, agglomerates, or clumps.\n169 Fineness of dispersion\n170 Dispersions of tablets in water prepared in the XTEMP-R device were tested for fineness of \n171 dispersion.\n172 TBAJ-876 and TBI-223\n173 One tablet was added to the XTEMP-R followed by 5 mL of water. The tablet was allowed to \n174 soak for 5 minutes, followed by 2 minutes of massaging in the XTEMP-R. The dispersion was \n175 poured through a #18 sieve (1000 µm opening) with a pan at the bottom for collecting the \n176 dispersion. This test was performed in triplicate by each of two analysts.\n177 Total dose recovery from tablet dispersion in XTEMP-R\n178 TBAJ-876\n179 The prepared 25 mL suspension in the XTEMP-R device was shaken 25 times and transferred to \n180 a 250 mL volumetric flask. The device was rinsed with 15 mL of water and the rinse was added \n181 to the volumetric flask with the suspension. This stock solution was diluted to volume with 1:1 \n182 acetonitrile:water. A sample of this stock solution was further diluted with diluent (Table 1) to a \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n183 concentration of 0.04 mg/mL. An aliquot of this diluted sample was filtered and analyzed by \n184 HPLC as described under Analytical test methods below.  The recovery was tested on three \n185 preparations.\n186 TBI-223\n187 The prepared 15 mL suspension in the XTEMP-R device was shaken 25 times and transferred to \n188 a 250 mL volumetric flask. The device was rinsed with 15 mL of water and the rinse was added \n189 to the volumetric flask with the suspension. A volume of 30 mL of acetonitrile was added to the \n190 flask and mixed. This stock solution was diluted with diluent (Table 1) to volume. A sample of \n191 this stock was further diluted with diluent to a concentration of 0.05 mg/mL. An aliquot of this \n192 sample was filtered and analyzed by HPLC as described under Analytical test methods below. \n193 The recovery was tested on three preparations.\n194 Dose reproducibility of aliquots of tablet dispersion in XTEMP-R\n195 A general technique for withdrawal of aliquots for partial doses is represented in Fig 3.\n196 Fig 3. Withdrawal of an Aliquot from XTEMP-R for Partial Dose of TBI-223 Suspension.\n197\n198 TBAJ-876\n199 Prior to withdrawal of the dose aliquot, a syringe adapter was attached to the opening of \n200 XTEMP-R and the device was capped. The prepared 25 mL suspension in the XTEMP-R device \n201 was shaken 25 times and a 3-mL oral syringe was attached to the syringe adapter. A 2-mL \n202 aliquot was removed for an 8-mg dose. The dose reproducibility was tested on three 2-mL \n203 aliquots withdrawn from the same preparation. For each withdrawal of the aliquot, the capped \n204 device was shaken to simulate the procedure that would be followed by the patient or \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n205 caregiver. This was repeated on three different preparations. Each 8-mg dose was diluted with \n206 diluent to a concentration of 0.04 mg/mL, filtered, and analyzed by HPLC. The remaining \n207 suspension in the XTEMP-R was left undisturbed on the bench for about 24 hours.  The \n208 preparations were redispersed by shaking and one aliquot from each preparation was \n209 withdrawn and tested.\n210 TBI-223\n211 Prior to withdrawal of the dose aliquot, a syringe adapter was fitted on to the device and the \n212 device was capped. The prepared 15 mL suspension in the XTEMP-R device was shaken 25 \n213 times and a 3-mL oral syringe was attached to the syringe adapter. A 2-mL aliquot was removed \n214 for an 80-mg dose. The dose reproducibility was tested on three 2-mL aliquots withdrawn from \n215 the same preparation. For each withdrawal of the aliquot, the capped device was shaken to \n216 simulate the procedure that would be followed by the patient or caregiver. This was repeated \n217 on three different preparations. Each dose withdrawn was transferred into a 100-mL volumetric \n218 flask. Acetonitrile 2 mL was added to the flask and swirled to mix the sample with the solvent. \n219 The mixture in the flask was then diluted with diluent to volume. An aliquot of 3 mL of this \n220 stock sample preparation was diluted to 50 mL to a concentration of 0.05 mg/mL. An aliquot of \n221 this sample preparation was filtered and analyzed by HPLC. The remaining suspensions in the \n222 XTEMP-R were left undisturbed on the bench for about 24 hours and an aliquot from each \n223 preparation was tested after redispersing.\n224 Analytical test methods for TBAJ-876 and TBI-223\n225 Stability-indicating validated HPLC methods were used for the potency testing of TBI-223 and \n226 TBAJ-876 suspensions. Details of the HPLC methods are provided in Table 1. \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n227 Table 1. Details of Stability-Indicating HPLC Methods for Potency Testing of TBI-223 and TBAJ-\n228 876 Suspensions.\nDetails\nParameter\nTBI-223 TBAJ-876\nInstrument\nHitachi L-2100 pump, Shimadzu SPD-10AVP detector, Shimadzu \nSCL-10AVP controller, Shimadzu CTO-AVP column heater, SRI \nInstruments PeakSimple chromatography data system\nColumn Zorbax Bonus RP (C18, 4.6 mm x \n150 mm, 3.5μm)\nWaters Symmetry Shield RP-8 \n(4.6 mm x 150 mm, 5μm)\nWavelength 258 nm 236 nm\nColumn Temp. 30 °C 40 °C\nFlow Rate 0.8 mL/min 2.0 mL/min\nInjection Volume 10 µL 5 µL\nSyringe filter 1.0 µm glass fiber filter 0.45 µm PVDF syringe filter\nStandard and sample \nConcentration 0.05 mg/mL 0.04 mg/mL\nMobile Phase\nMobile Phase-A: \n0.05% TFA in water\nMobile Phase-B: \n0.05% TFA in Acetonitrile\n0.01M Ammonium acetate: \nAcetonitrile (1:3)\nDiluent 0.2% SLS in Water:Acetonitrile \n(1:1) Water:Acetonitrile (1:4)\nRun Time\n8 minutes\n(Gradient: 0.0-2.0 mins: A:64% \nand B:36%; 2.0-4.5 mins: A:64% \nand B:36% to A:46% and B:54%; \n4.6-8.0 mins: A:64% and B:36%)\n7 minutes\n(Isocratic)\nPeak retention time About 3.6 minutes About 4.4 minutes\nIntegration\nPeak area method using \nPeakSimple data acquisition \nsystem\nPeak area method using \nPeakSimple data acquisition \nsystem\n229\n230 TBAJ-876 quantification method validation\n231 The method was validated for specificity (placebo interference and forced degradation), \n232 linearity, filter study, precision (system suitability and repeatability), and accuracy according to \n233 International Conference on Harmonization (ICH) guidelines [10]. Specificity was assessed to \n234 verify the absence of interference from tablet excipients, and suspension matrix and to \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n235 establish the analyte peak does not interfere with the possible degradants of the forced \n236 degradation of samples. Seven-point calibration curve was constructed with standard solutions \n237 in the range of 50% (20 μg/mL) to 150% (60 μg/mL) of standard concentration i.e., 40 μg/mL. \n238 TBI-223 quantification method validation\n239 The method was validated for specificity (placebo interference and forced degradation), \n240 linearity, filter study, precision (system suitability and repeatability), and accuracy according to \n241 ICH guidelines. Specificity was assessed to verify the absence of interference from tablet \n242 excipients, and suspension matrix and to establish the analyte peak does not interfere with the \n243 possible degradants of the forced degradation of samples. Five-point calibration curve was \n244 constructed with standard solutions in the range of 50% (25 μg/mL) to 150% (75 μg/mL) of \n245 standard concentration i.e., 50 μg/mL. \n246 Dispersions of commercial tablets prepared in XTEMP-R\n247 We tested five different commercially available tablets to determine effectiveness of the \n248 XTEMP-R device in producing a fine dispersion that passed through a #18 sieve (1000 um \n249 opening). The commercial tablets were selected to represent small and large tablets. \n250 Manufacturer details, composition, tablet weight and drug content of the commercial tablets \n251 tested are provided in Table 2. Metformin tablets were included for evaluation to challenge the \n252 dispersing functionality of the XTEMP-R device, as they represent high dose, and high drug load \n253 tablets with a high drug to excipient ratio.\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n254 We tested the dispersibility of these commercial tablets by using the same methodology of \n255 soaking them in water for 5 minutes and massaging for 2 minutes, similar to the TBAJ-876 and \n256 TBI-223 tablets. The suspensions were tested for fineness of dispersion.\n257 We also tested these commercial tablets for the shortest massaging time that could accomplish \n258 dispersion for fineness. One tablet was added to the XTEMP-R followed by 5 mL of water and \n259 massaged in the XTEMP-R device until the analyst felt that the tablet was completely dispersed, \n260 and the time was recorded. The suspension was poured through a #18 sieve (1000 µm opening) \n261 with a pan at the bottom for collecting the dispersion. This test was performed in triplicate by \n262 each of two analysts.\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n263\n264 Table 2. Commercial Tablets Tested for Dispersion Times for Fineness of Dispersion.\nProduct Manufacturer NDC Inactive Ingredients Tablet Weight (mg) % Drug in Tablet\nValsartan 320 mg MacLeods 33342-065-10\nColloidal silicon dioxide, crospovidone*, \nhypromellose, iron oxides (yellow, black \nand/or red), microcrystalline cellulose, \nmagnesium stearate, polyethylene glycol, talc \nand titanium dioxide\n1030 31.1\nAcetaminophen 500 \nmg (Tylenol®) McNeil 50580-449-96\nCarnauba wax, corn starch, FD&C red no. 40 \naluminum lake, hypromellose, magnesium \nstearate, modified starch, polyethylene \nglycol, powdered cellulose, pregelatinized \nstarch, propylene glycol, shellac, sodium \nstarch glycolate*, titanium dioxide\n610 82.0\nGlimepiride 2 mg Accord 16729-002-01\nLactose monohydrate, sodium starch \nglycolate*, povidone, and magnesium \nstearate. Ferric oxide yellow and FD &C blue \n#2 aluminum lake\n170 1.2\nAmlodipine 2.5 mg Ascend 67877-197-90\nMicrocrystalline cellulose, dibasic calcium \nphosphate anhydrous, sodium starch \nglycolate*, colloidal silicon dioxide and \nmagnesium stearate\n100 2.5\nMetformin 1000 mg Ascend 67877-563-01\nPovidone (K-30), povidone (K-90), \npregelatinized starch*, and magnesium \nstearate. Coating: artificial blackberry flavor, \nhypromellose and polyethylene glycol.\n1080 92.6\n265 *disintegrant \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n266 Results\n267 Preparation of suspensions from tablets using XTEMP-R\n268 TBAJ-876 and TBI-223\n269 The suspension preparation technique for the two tablets, TBAJ-876 and TBI-223, was found to \n270 be simple, efficient and could be performed well in this closed system. The suspensions were \n271 prepared in less than 10 minutes without any complicated, tedious, or messy steps. The details \n272 of the suspension evaluation are provided below. \n273 Evaluation of suspensions prepared in XTEMP-R\n274 Visual observation\n275 TBAJ-876 and TBI-223\n276 Fig 4 shows the visual appearance of the suspensions of the two drugs, TBI-223 and TBAJ-876. \n277 Both suspensions had uniform appearance and the particles were observed to be \n278 homogeneously dispersed. TBI-223 suspension was observed to be milky white, opaque, and \n279 uniform when light was shown from below the watch glass containing the suspension. TBAJ-876 \n280 suspension was translucent with distinct particles visible and uniformly dispersed. The \n281 appearance of the suspension as translucent or opaque is dependent on the ingredients and \n282 composition of the tablets and the dispersion vehicle. \n283 Fig 4. Visual Observation of Suspensions Prepared in XTEMP-R. (a) Appearance of TBAJ-876 \n284 suspension, (b) TBAJ-876 suspension in XTEMP-R device, (c) Appearance of TBI-223 suspension, \n285 (d) TBI-223 suspension in XTEMP-R device.\n286\n287 Fineness of dispersion\n288 TBAJ-876 and TBI-223\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n289 The dispersions prepared with 5-minute soaking and 2-minute massaging times in the XTEMP-R \n290 device passed through the #18 sieve. No particles were retained indicating that all particles \n291 were below 1000 µm and dispersed particles were not forming aggregates or agglomerates. \n292 Total dose recovery from tablet dispersion in XTEMP-R\n293 TBAJ-876 and TBI-223\n294 The total dose recovered from the triplicate preparations of TBAJ-876 and TBI-223 in XTEMP-R \n295 are presented in Table 3. The recovery of TBAJ-876 from three distinct preparations in XTEMP-R \n296 ranged from 98.8-100.0% with an average recovery of 99.2%. The recovery of TBI-223 from \n297 three distinct preparations in XTEMP-R ranged from 100.4-102.9% with an average recovery of \n298 101.3%. These ranges include inherent tablet-to-tablet content variability as well as analytical \n299 variability.\n300\n301 Table 3. Recovery of TBI-223 and TBAJ-876 from Suspensions Prepared in XTEMP-R.\nTablet Suspending \nAgent\nDispersion time \n(minutes)\nPreparation Total Recovered (%) from \nentire contents in device\n1 98.8\n2 100.0\n3 99.0TBAJ-876 Water + ORA-\nSweet\n5 minutes soak+2 \nminutes massage\nAverage (RSD) 99.2 (0.64)\n1 100.4\n2 100.5\n3 102.9TBI-223 Water + ORA-\nBlend\n5 minutes soak+2 \nminutes massage\nAverage (RSD) 101.3 (1.4)\n302 RSD = relative standard deviation\n303 Dose reproducibility of aliquots of tablet dispersion in XTEMP-R\n304 TBAJ-876 and TBI-223\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n305 The results for dose reproducibility are provided in Table 4. Average potency of three \n306 suspensions from three replicate aliquots of 2-mL from each suspension were found to be \n307 98.9-99.7% for TBI-223 suspensions, and 102.6-103.2% for TBAJ-876 suspensions. The potency \n308 of an additional aliquot withdrawn after redispersing after 24 hours from each of the three \n309 suspensions was found to be 96.0-100.3% for TBAJ-876 suspensions and 99.3-100.3% for \n310 TBI-223 suspensions.\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n311\n312 Table 4. Dose Reproducibility of Aliquots Withdrawn from TBAJ-876 and TBI-223 Suspensions.\nTheoretical dose dispensed (%)Tablet Suspending Agent\nAliquot Preparation 1 Preparation 2 Preparation 3\nTBAJ-876 Water + ORA-Sweet 99.2 101.2 102.2\n104.5 102.5 104.3\nDay 0\n105.7 104.2 103.0\nAverage (RSD) 103.1 (3.44) 102.6 (1.44) 103.2 (0.99)\nDay 1 96.0 100.3 98.2\nTBI-223 Water + ORA-Blend 99.4 98.8 99.9\n98.5 98.9 99.8\nDay 0\n99.3 98.9 99.5\nAverage (RSD) 99.1 (0.5) 98.9 (0.1) 99.7 (0.2)\nDay 1 100.3 99.3 100.2\n313 RSD = relative standard deviation\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n314 TBAJ-876 tablets test method validation\n315 The seven-point calibration curve in the range of 20 μg/mL to 60 μg/mL was linear with a high \n316 correlation coefficient (r) of 1.000. For both standard and sample tests, % RSD for inter- and \n317 intra-day precision were well below 2%, and mean recovery was well within the range of 98% to \n318 102%. \n319 TBI-223 tablets test method validation\n320 The five-point calibration curve in the range of 25 μg/mL to 75 μg/mL was linear with a high \n321 correlation coefficient (r) of 1.000. For both standard and sample tests, % RSD for precision \n322 were well below 2%, and mean recovery was well within the range of 98% to 102%. \n323 Dispersions of commercial tablets prepared in XTEMP-R\n324 The suspensions prepared with 5-minute soaking and 2-minute massaging times in the \n325 XTEMP-R device passed through the #18 sieve. No particles were retained indicating that all \n326 particles were below 1000 µm and dispersed particles were not forming aggregates or \n327 agglomerates. \n328 The earliest dispersion times for all commercial tablets tested ranged from 1-3 minutes except \n329 for metformin which did not disintegrate within the time tested (10 minutes soaking and 5 \n330 minutes massaging). The dispersion times presented in Table 5 represent the dispersion time \n331 for the suspensions prepared by two independent analysts that passed the fineness of \n332 dispersion test.\n333 The drug content (labelled dose of the drug in total tablet weight) and disintegrant in each \n334 tablet formulation are provided in Table 2. Except for metformin, all other tablet formulations \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n335 contained superdisintegrants. Valsartan, acetaminophen, and metformin had 31, 82, and 93% \n336 of drug load, respectively. Glimepiride and amlodipine contained 1.2 and 2.5% of drug load, \n337 respectively.\n338 Table 5. Dispersion Times of Commercial Tablets.\nTablet Dispersion Time (min) in X-TEMP-R\nValsartan 1.5\nAcetaminophen 3\nGlimepiride 3\nAmlodipine 1\nMetformin >10*\n339 *Did not disperse in time tested (10 minutes soaking and 5-minute massaging)\n340 Discussion\n341 Tablet splitting, crushing, and grinding is a common practice for medication administration. The \n342 necessity for splitting or crushing tablets arises from the need to administer drug doses other \n343 than that are available in tablet formulations, as well as facilitate the swallowing of tablets [11]. \n344 There have been some challenges identified with both, tablet splitting and tablet pulverization. \n345 Large deviations of dose can occur due to unequal fragments of split tablets or weight \n346 differences due to loss of powdered or chipped material resulting from the splitting process [9]. \n347 Tablet crushing can result in significant drug loss [5]. Some crushing devices yield large particles \n348 that cannot be administered via a feeding tube [4]. Aerosolized powder during crushing and \n349 grinding can be an environmental [2] and health hazard.\n350 This paper describes a procedure for converting tablets into a suspension: (1) that is simple and \n351 reproducible; (2) where tablet disintegration and preparation of suspension is performed within \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n352 the same device; (3) in a contained environment; (4) that enables measurement and \n353 withdrawal of any required dose with accuracy; (5) with small particle size that permits \n354 administration through feeding tubes; and (6) where consumption is possible from the same \n355 receptacle.\n356 XTEMP-R is a simple mechanical device designed to facilitate and expedite the disintegration \n357 and dispersion of tablets in a small volume (<10 mL) of water. This device is constructed with \n358 low hardness silicone, making it pliable yet durable. It can be gently squeezed by fingers to \n359 facilitate the dispersion of the tablet. This squeezing and massaging action facilitated the \n360 interaction of water with the superdisintegrants present in the tablet, thus promoting its \n361 dispersion. These ingredients are routinely included in the tablet formulations to aid in the \n362 break-up of the compacted mass.\n363 The disintegration and suspension of tablets in the XTEMP-R device occurs in the same \n364 container in a closed environment. Therefore, there is minimal risk of any drug loss during the \n365 preparation. The XTEMP-R container does not have any cutting or grinding parts. It is also safer \n366 for caregivers to prepare the suspension with XTEMP-R since there is minimal contact with the \n367 drug either by touch or by inhalation of drug powder that may get aerosolized during \n368 pulverization.\n369 Both TBAJ-876 and TBI-223 tablets are investigational drugs under IND applications with \n370 established specifications and content uniformity standards. As demonstrated by the results, \n371 TBAJ-876 and TBI-223 tablets could be dispersed homogenously in water and suspending \n372 vehicle within 10 minutes. Accurate aliquots could be withdrawn reproducibly from the device \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n373 immediately after the preparation and 24 hours later. We withdrew aliquots from each \n374 preparation sequentially after preparation and on the following day after redispersing by \n375 shaking. This closely simulates what would occur in the pharmacy, at the patient’s home or at \n376 the clinical investigation site. The partial doses withdrawn for the suspension were uniform and \n377 stable as they could be redispersed reproducibly after 24 hours.  It was not our intent to \n378 prepare suspensions for long term storage.\n379 Fineness of dispersion was one of the quality criteria. The suspensions were tested by passing \n380 them through a #18 sieve (1000 µm aperture). Our objective was to ensure that no particle \n381 agglomerates were present in the suspension and that the largest particles in the suspension \n382 could be suspended in commonly available suspending vehicles. Bowles and colleagues [13] \n383 have demonstrated that particles up to 1000 µm can be successfully suspended with the aid of \n384 commonly used suspending vehicles.\n385 Drug loss is one of the challenges when the tablets are pulverized before dispersing in a \n386 suspension. Drug powder tend to stick to the walls of the container such as a mortar and pestle. \n387 Thong and colleagues [5] have recommended two rinses of the tablet crushing devices to \n388 ensure minimum drug loss. Close to 100% of active drug from all three suspensions of TBAJ-876 \n389 and TBI-223 prepared by the XTEMP-R device was recovered. The devices were only rinsed once \n390 with 15 mL of water for each preparation. The total dose could be ingested directly from the \n391 device avoiding a transfer to a dispensing container. This methodology offers an alternative \n392 dose administration option for patients suffering from dysphagia.\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n393 We have also investigated the applicability of this device for some commercial tablets. Except \n394 for metformin, the tablets could be dispersed by soaking for 5 minutes and massaging for 2 \n395 minutes. For some products, the dispersion could be faster by just massaging for 1-3 minutes. \n396 The metformin tablets had a high drug load with just about 8% excipients and did not contain \n397 any superdisintegrants. Desai and colleagues [14] studied metformin formulation with minimal \n398 excipients and concluded that even for a highly soluble drug, a superdisintegrant was needed in \n399 the formulation to change the dissolution mechanism from erosion-diffusion to disintegration. \n400 Masum and colleagues [15] formulated metformin tablets with different disintegrants and \n401 found that the wetting time, dispersion time and the disintegration time of metformin tablets \n402 were governed by the type and quantity of the superdisintegrants. In the XTEMP-R device, the \n403 volume of the dispersing vehicle (5-7 mL water) and massaging are not sufficient to have \n404 effective erosion-diffusion for the tablet to dissolve or disperse the metformin tablet. \n405 Therefore, the use of the XTEMP-R device may be limited for tablets that depend primarily on \n406 solubilization for dissolution and do not contain effective disintegrants. These observations \n407 corroborate our assumption that XTEMP-R promotes the interaction between water and tablet \n408 formulations. The ingredients of each tablet formulation can be found in the product \n409 prescribing information.\n410 The lack of child-friendly formulations leaves 40% of the world population at increased risk for \n411 preventable adverse events, suboptimal dosing, noncompliance, and lack of access to new \n412 medicines [16]. In some instances, the caregiver is required to administer a quarter of a tablet \n413 to a neonate. XTEMP-R device may offer an alternative for accurate dosing in this patient \n414 population. Of course, appropriate development and analytical work will have to be performed. \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n415 Fortunately, several publications [17,18] describing the compatibility of drugs that lack pediatric \n416 formulations with commonly available suspending agents and with established storage \n417 conditions and shelf life are available.\n418 Limitations\n419 XTEMP-R device worked well with the tablets containing superdisintegrants in the formulation.  \n420 This device, however, may not work well with certain large tablets with a high drug-to-excipient \n421 ratio and/or tablets not containing effective disintegrants in the formulation. This will have to \n422 be tested on a case-by-case basis.\n423 This device does not offer protection from light. Photosensitive drug preparations should be \n424 stored in the device with added protection from light.\n425 The silicone material of the XTEMP-R device may be stained from a colored drug dispersion. \n426 Therefore, it is recommended that a dedicated device should be used for colored drugs such as \n427 clofazimine.\n428 Dose preparation may be challenging for patients that are unable to massage the tablet in the \n429 device. XTEMP-ETM, another version of XTEMP-R is equipped with an electronic mechanism for \n430 mixing.  XTEMP-E will be presented in a subsequent publication.\n431 The utility of this device and methodology for suspending any tablet formulation has to be \n432 supported by appropriate development and analytical work. As exemplified by the work \n433 conducted for TBAJ-876 and TBI-223 in this paper, similar rigor is recommended for any other \n434 drug that will utilize XTEMP-R for suspension.\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n435 Conclusion\n436 We have demonstrated that the new XTEMP-R device can be utilized for aliquoting partial \n437 doses of TBAJ-876 and TBI-223 immediate release tablets. Homogeneous suspensions could be \n438 prepared conveniently, safely, and expeditiously without any significant loss. Further, this \n439 device has the potential to offer an alternative for dosing patients who cannot ingest \n440 immediate release tablets. This could be beneficial to pediatric and elderly patients, intubated \n441 patients, and patients with dysphagia. Additional work is required to establish the utility of the \n442 device for other immediate release tablets.\n443 Acknowledgements\n444 The authors are grateful for the funding provided by TB Alliance.\n445 References\n446 1. Ranked: The most prescribed drugs in the U.S. by Omri Wallach, Graphics/Design: \n447 Amy Realey; 2021 Nov 1; https://www.visualcapitalist.com/ranked-the-most-\n448 prescribed-drugs-in-the-u-s/. (accessed 2021 Dec 12).\n449 2. Damien Salmon, Elisa Pont, Hélène Chevallard, Elhadji Diouf, Mamadou-Lamine Tall, \n450 Christine Pivot, Fabrice Pirot, Pharmaceutical and safety considerations of tablet \n451 crushing in patients undergoing enteral intubation, International Journal of \n452 Pharmaceutics, Volume 443, Issues 1–2, 2013, Pages 146-153, ISSN 0378-5173, \n453 https://doi.org/10.1016/j.ijpharm.2012.12.038. \n454 3. Diana A. van Riet Nales, Piotr Kozarewicz, Siri Wang, Agnes Saint-Raymond, Jean-\n455 Louis Robert, Comments on the EMA draft guideline: Final steps towards a \n456 harmonized view between regulators and industry, International Journal of \n457 Pharmaceutics, Volume 457, Issue 1, 2013, Pages 337-339, ISSN 0378-5173, \n458 https://doi.org/10.1016/j.ijpharm.2013.08.060.\n459 4. Woerdenbag HJ, Visser JC, Leferink Op Reinink MPAM, van Orsoy RR, Eissens AC, \n460 Hagedoorn P, Dijkstra H, Allersma DP, Ng SW, Smeets OSNM, Frijlink HW. \n461 Performance of Tablet Splitters, Crushers, and Grinders in Relation to Personalised \n462 Medication with Tablets. Pharmaceutics. 2022 Jan 28;14(2):320. doi: \n463 10.3390/pharmaceutics14020320. PMID: 35214052; PMCID: PMC8878961.\n464 5. Thong MY, Manrique YJ, Steadman KJ (2018) Drug loss while crushing tablets: \n465 Comparison of 24 tablet crushing devices. PLOS ONE 13(3): e0193683. \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n466 https://doi.org/10.1371/journal.pone.0193683; PMID: 29494695; PMCID: \n467 PMC5832315.\n468 6. Helmy SA. Tablet splitting: is it worthwhile? Analysis of drug content and weight \n469 uniformity for half tablets of 16 commonly used medications in the outpatient \n470 setting. J Manag Care Spec Pharm. 2015 Jan;21(1):76-86. doi: \n471 10.18553/jmcp.2015.21.1.76. PMID: 25562775.\n472 7. Starling, Flavio & Camargos, Einstein & Ferreira, Felipe & Polo, Marco & Freitas, \n473 Marco Polo & Costa, Reinaldo & Medeiros-Souza, Patricia. (2019). UNAVAILABILITY \n474 OF APPROPRIATE DOSES AND NEED FOR TABLET SPLITTING OF PSYCHOTROPIC \n475 DRUGS BY GERIATRIC PATIENTS Indisponibilidade de doses apropriadas e \n476 necessidade de fracionamento de medicamentos psicotrópicos por pacientes \n477 geriátricos. Geriatr Gerontol Aging. 2019;13(3):126-32.\n478 8. Freeman MK, White W, Iranikhah M. Tablet splitting: a review of weight and content \n479 uniformity. Consult Pharm. 2012 May;27(5):341-52. doi: 10.4140/TCP.n.2012.341. \n480 PMID: 22591978.\n481 9. Verrue C, Mehuys E, Boussery K, Remon JP, Petrovic M. Tablet-splitting: a common \n482 yet not so innocent practice. J Adv Nurs. 2011 Jan;67(1):26-32. doi: 10.1111/j.1365-\n483 2648.2010.05477.x. PMID: 21158902.\n484 10. International Conference on Harmonisation of Technical Requirements for \n485 Registration of Pharmaceuticals for Human Use (ICH). Guidance for Industry, Q2B \n486 Validation of Analytical Procedures: Methodology. 1996, ICH-Quality final guidance \n487 FDA issue date 1997. https://www.fda.gov/regulatory-information/search-fda-\n488 guidance-documents/q2b-validation-analytical-procedures-methodology\n489 11. Pahwa, R, Gupta, N. Superdisintegrants in the development of orally disintegrating \n490 tablets: a review. Int J Pharm Sci Res 2010; 2: 2767-80. \n491 http://dx.doi.org/10.13040/IJPSR.0975-8232.2(11).2767-80\n492 12. Markl D, Zeitler JA. A Review of Disintegration Mechanisms and Measurement \n493 Techniques. Pharm Res. 2017 May;34(5):890-917. doi: 10.1007/s11095-017-2129-z. \n494 Epub 2017 Mar 1. PMID: 28251425; PMCID: PMC5382187.\n495 13. Bowles, A., Ernest, T., Clapham, D., & Tuleu, C. (2010, November). Evaluation of the \n496 rheological and suspending properties of commonly used oral suspending vehicles. \n497 Poster presented at International Pharmaceutical Federation World \n498 Congress/Annual Meeting American Association of Pharmaceutical Scientists, New \n499 Orleans, USA\n500 14. Desai D, Wong B, Huang Y, Tang D, Hemenway J, Paruchuri S, Guo H, Hsieh D, \n501 Timmins P. Influence of dissolution media pH and USP1 basket speed on erosion and \n502 disintegration characteristics of immediate release metformin hydrochloride tablets. \n503 Pharm Dev Technol. 2015;20(5):540-5. doi: 10.3109/10837450.2014.892132. Epub \n504 2014 Mar 12. PMID: 24621340.\n505 15. Masum MA et al., Effect of Superdisintegrants on Physical Attribute and Release \n506 Profile of Metformin HCl Immediate Release Tablets. American Journal of \n507 PharmTech Research 2013; 3(1):1025-1036. ISSN:2249-3387\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n508 16. Milne CP, Bruss JB. The economics of pediatric formulation development for off-\n509 patent drugs. Clin Ther. 2008 Nov;30(11):2133-45. doi: \n510 10.1016/j.clinthera.2008.11.019. PMID: 19108801.\n511 17. Jew RK, Soo-Hoo W, Erush SC, et al. Extemporaneous formulations for pediatric, \n512 geriatric, and special needs patients, 3rd ed. ASHP, 2016.\n513 18. Nahata, MC, Pai, VB. Pediatric drug formulations, 7th ed. Harvey Whitney Books \n514 Company, 2018.\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n516 Supporting Information\n517 Link to video for suspension preparation methodology\n518 https://www.dropbox.com/sh/t0bj2o6ivjuh8l3/AAAZe3mRxc1HImGlbpoFDUUua?dl=0\n519 S1 Fig. Representative chromatograms of TBAJ-876 analysis (a) Standard 1, (b) Diluent blank, \n520 (c) Day 0 aliquot for dose reproducibility, (d) Day 0 suspension matrix blank (diluent + ORA-\n521 Sweet), (e) Day 1 aliquot for dose reproducibility, (f) Day 1 suspension matrix blank (diluent + \n522 ORA-Sweet), (g) Standard 2, (h) Total dose recovery\n523 S2 Fig. Representative chromatograms of TBI-223 analysis (a) Standard 1, (b) Diluent blank, (c) \n524 Day 0 aliquot for dose reproducibility, (d) Day 0 suspension matrix blank (diluent + ORA-Blend), \n525 (e) Day 1 aliquot for dose reproducibility, (f) Day 1 suspension matrix blank (diluent + ORA-\n526 Blend), (g) Standard 2, (h) Total dose recovery\n527\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\nAuthor contributions\nRajneesh Taneja conceptualized and designed the device and experiments\nJoseph Scarim conceptualized and designed the device and experiments\nPoonam G Pande designed and coordinated the testing, corresponding author\nAnthony Scarim conducted the analytical work\nMilap C Nahata consulted on the utility of the device\nRita K Jew consulted on the utility of the device\nKoteswara Inabathina coordinated the device manufacture\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint \n\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint","source_license":"CC-BY-4.0","license_restricted":false}