An Alternative Approach to Tablet Splitting and Grinding for Medication Administration

1 RESEARCH ARTICLE 2 Title: An Alternative Approach to Tablet Splitting and Grinding for Medication Administration 3 4 Rajneesh Taneja1, Joseph Scarim2, Poonam G Pande1*, Anthony Scarim2, Milap C Nahata3, Rita K 5 Jew4, Koteswara Inabathina1 6 7 1Global Alliance for TB Drug Development (TB Alliance); 2JSAS Services Inc; 3Institute of 8 Therapeutic Innovations and Outcomes, Colleges of Pharmacy and Medicine, The Ohio State 9 University; 4Institute for Safe Medication Practices (ISMP) 10 11 *Correspondence 12 Poonam Pande, TB Alliance, 40 Wall Street, 24th Floor, New York, NY 10005 13 e-mail: [email protected] 14 15 Running head: Alternative method for suspending oral tablets 16 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 17 Abstract 18 Purpose. Tablet formulations fail to meet the needs of patients unable to swallow tablets such 19 as pediatric, elderly, and patients that must receive medications via feeding tubes. Our aim was 20 to develop and test a new, simple device (XTEMP-RTM) and the methodology for converting 21 tablets into a homogeneous suspension for medication administration. 22 Methods. We developed a new device comprised of a flexible receptacle, a tight-fitting cap, and 23 a suction cup bottom to convert tablets into liquid preparations. TB treatment drugs, TBAJ-876 24 and TBI-223, were dispersed within the device utilizing water and commonly available 25 suspending vehicles. We investigated the effectiveness of the XTEMP-R device in dispersing 26 tablets. This was accomplished by visual observations, determining the fineness of dispersion, 27 and measuring the total drug recovery from the dispersions in XTEMP-R. We investigated the 28 accuracy and reproducibility of delivering aliquots from these suspensions by determining the 29 dose reproducibility upon suspension and upon redispersion after 24 hours. The effectiveness 30 of the device was also evaluated using commercially available tablets of acetaminophen, 31 amlodipine, glimepiride, metformin and valsartan. 32 Results. The suspensions were visually uniform without any large particles. The suspensions 33 passed through #18 sieve confirming that the particles were less than 1000 µm. Average total 34 dose recovery of three suspensions each was determined to be 101.3% and 99.2% for TBI-223 35 and TBAJ-876, respectively. Reproducibility from aliquots of 2 mL each were 98.9-99.7% for 36 three replicates of TBI-223 suspensions, and 102.6-103.2% for TBAJ-876 suspensions. Aliquots 37 tested after 24 hours confirmed uniform re-dispersibility. . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 38 Conclusion. We have demonstrated that XTEMP-R can be utilized to prepare homogeneous 39 suspensions can be prepared conveniently and efficiently in less than 10 minutes without any 40 drug loss. Aliquots for partial dose delivery can be withdrawn accurately. These findings 41 demonstrate that XTEMP-R can be used to accurately deliver doses of suspensions for patients 42 who cannot swallow tablets. 43 44 Keywords: aliquot, device, dosing, dysphagia, geriatric, pediatric, suspension 45 46 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 47 Introduction 48 Tablets remain the most common modality for oral dose administration of drugs. They 49 represent 28 of the top 30 prescription drugs in 2021 [1]. However, these formulations are not 50 suitable for some patients, especially young children, and those suffering from dysphagia. 51 Tablet administration is also a challenge for patients receiving enteral tube feeding [2]. If an 52 alternate oral formulation or route of administration is unavailable, manipulation of the dosage 53 form may be undertaken at the point of administration to provide the prescribed dose [3]. 54 Manipulation involves physical alteration of the dosage form, including tablet splitting, 55 crushing, or grinding [4]. Dose adjustment is commonly achieved through tablet splitting, 56 whereas tablet crushing or grinding aid the swallowing or administration via an enteral feeding 57 tube [4]. 58 Tablets are often pulverized (crushed or ground) with a mortar and pestle or other tablet 59 grinding device to facilitate administration [2,5]. However, this process is tedious and often 60 leads to the loss of the prescribed dose during preparation or administration [5]. In one study, it 61 was demonstrated that two rinses of the grinding devices with water were required to prevent 62 significant drug loss [5]. Screwcap crushers yield larger particles that are not suited for feeding 63 tube administration [4]. Also, some hazardous drugs may pose risks to caregivers preparing the 64 doses through the inhalation of generated powder containing the drug, or through contact with 65 skin, nose, and eyes [4]. 66 Another common practice is tablet splitting [6,7]. It is used for many reasons including 67 delivering partial dose of the tablet, facilitating swallowing, or cost savings [8,9]. However, this . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 68 process raises the issues of drug loss, variation in dose uniformity, dose accuracy, and weight 69 uniformity between fragments [8]. Many tablets may not be suitable for splitting due to factors 70 such as hardness, size, shape, or absence of score line. 71 Steadman and colleagues [5] called for a device that minimizes drug loss and maximizes 72 medication delivery, i.e., a device that ensures a sealed environment for crushing followed by 73 mixing with a fluid and subsequent consumption from the same receptacle [5]. Salmon and 74 colleagues [2] expressed a need for a combined crushing and suspending device. 75 TBAJ-876 (US IND number 145,349) and TBI-223 (US IND Number 134,334) are two new 76 chemical entities under development as immediate-release tablets for the treatment of 77 tuberculosis. The tablets are available in 100 mg and 600 mg strengths, respectively. Dose 78 titration is required while conducting early clinical studies with these drugs. A liquid 79 formulation allows for the flexibility of aliquoting the desired dose in any fraction. The 80 alternative is to manufacture tablets in multiple strengths and choose a combination of 81 different strength tablets for the desired dose. 82 The objective of our work was to develop a device and methodology that enabled the 83 dispersion of TBI-223 and TBAJ-876 immediate-release tablets into a suspension in water 84 without the need for crushing or grinding in a contained environment. Further, a suspending 85 vehicle can be added to make it into a homogenous suspension that allows for accurate partial 86 dose delivery. 87 A new, simple device (XTEMP-RTM) was developed, and the methodology for converting tablets 88 into a homogeneous suspension with this device is described in this paper. This device and . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 89 methodology can be used in any setting without crushing, grinding, or splitting the tablet 90 dosage form. Flavors and sweeteners may be added to the suspension for enhancing 91 palatability. Our work is not suited for modified release, delayed-release, or controlled-release 92 tablets and capsules. In this paper, the term tablet refers to immediate-release tablet. The term 93 dispersion refers to the disintegration of the tablet in a liquid media resulting in a suspension. 94 The terms dispersion and suspension convey the same meaning. 95 To demonstrate the utility of the XTEMP-R device, we investigated (a) time to disperse the 96 tablets, (b) fineness of dispersion, (c) total dose recovery, and (d) accuracy of delivering aliquots 97 from suspensions. 98 In addition to TBAJ-876 and TBI-223, the dispersibility of a few commercial tablets was also 99 conducted to verify the utility of this device. 100 Materials and methods 101 Drugs and vehicles 102 TBI-223 IR tablets, 600 mg, TB Alliance, lot 6767AU01, retest 11/2022 103 TBAJ-876 Tablets, 100 mg, TB Alliance, Batch 6767BG01, retest 10/2022 104 Valsartan tablets, USP, 320 mg (Macleods, lot EVI2032A, exp 07/2022) 105 Tylenol® (acetaminophen) extra-strength tablets, 500 mg (Johnson & Johnson, lot AFA111, exp 106 05/2025) 107 Metformin tablets, USP, 1000 mg (Ascend, lot 4200094A, exp 07/2023) 108 Glimepiride tablets, USP, 2 mg (Accord, lot P2005847, exp 10/2023) 109 Amlodipine tablets, USP, 2.5 mg, (Ascend, lot 21140696, exp 01/2024) 110 ORA-Blend®, Perrigo, lot 2077398, exp. 28 Feb 2025 111 ORA-Sweet®, Perrigo, lot 1346049, exp 31 July 2024 112 Water, Distilled, Culligan, R22075 06:56 L1 Best By 03/2023 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 113 114 Chemicals 115 Acetonitrile, HPLC, Spectrum Chemical Mfg. Corp, item HP412, lot 20020323 116 Water, HPLC, Concord Technology, 8003LC4000, lot 201222 117 Ammonium Acetate, Sigma-Aldrich, item 73594-25G-F, lot BCCH0197 118 Trifluoroacetic acid (TFA), HPLC grade, Sigma-Aldrich, item 91707-10X1ML, lot bccg6537 119 Sodium lauryl sulfate (SLS), Sigma-Aldrich, Reagent grade, item 436143, lot MKCQ6608 120 121 Equipment and supplies 122 HPLC: Hitachi L-2100 pump, Shimadzu SPD-10AVP detector, Shimadzu SCL-10AVP controller, 123 Shimadzu CTO-AVP column heater, SRI Instruments PeakSimple chromatography data system 124 Column: Zorbax Bonus RP (C18, 4.6 mm x 150 mm, 3.5μm) 125 Column: Waters Symmetry Shield RP-8 (4.6 mm x 150 mm, 5μm) 126 Syringe Filters, Tisch Scientific, Glass Fiber, Hydrophilic, 25mm, 1.0um, PN SF14699, lot 127 170420083 128 Syringe Filters, PALL Life Sciences, PVDF, 13mm, 0.45um, PN 4545, lot A10648946 129 130 XTEMP-RTM device 131 XTEMP-R comprises a flexible receptacle, a tight-fitting cap, and a suction cup bottom (Fig 1). It 132 is a soft walled device manufactured with biocompatible, low hardness HCR (high-consistency 133 silicone rubber) sourced from Wacker, Germany. The construction material, platinum-cured 134 silicone, complies with FDA 21 CFR 177.2600, German Bfr XV, France Arrete Du 25, ROHS, 135 TSE/BSE free, USP Class VI Certification, and ISO 10993 Certification. These devices are 136 produced by a compression molding process (Ami Polymers Pvt. Ltd., India) in a class 10000 137 cleanroom. The height of the XTEMP-R device is 140 mm, the internal diameter is 22 mm, and 138 the capacity is approximately 40 mL. The device has volume markings on the outside at 5-mL . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 139 intervals starting at 15 mL. This device is resistant to extremes of environments and 140 temperatures and is designed to be leak-resistant and is easy to squeeze between the fingers 141 for manual dispersion of the tablets. 142 Fig 1. X-TEMP-RTM Device. 143 144 Preparation of suspensions from tablets using XTEMP-R 145 The general preparation technique is displayed in Fig 2 with preparation of TBI-223 suspension 146 as an example. 147 Fig 2. Preparation of TBI-223 Suspension from Tablets. 148 149 TBAJ-876 150 One tablet of TBAJ-876 100 mg was added to the XTEMP-R followed by 5 mL of water. The 151 device was capped and swirled for 5 seconds and left undisturbed for 5 minutes. Then the 152 tablet was manually massaged in the XTEMP-R for 2 minutes. ORA-Sweet suspending vehicle, 153 19.5 mL was added to the dispersion in the XTEMP-R make a final volume that coincided with 154 the 25-mL mark on the device and a final concentration of 4 mg/mL. The device was capped 155 and shaken 25 times to mix thoroughly. For redispersion, the suspension was shaken 25 times. 156 TBI-223 157 One tablet of TBI-223 600 mg was added to the XTEMP-R followed by 5 mL of water. The device 158 was capped and swirled for 5 seconds and left undisturbed for 5 minutes. Then the tablet was 159 manually massaged in the XTEMP-R for 2 minutes. ORA-Blend suspending vehicle, 9.4 mL was 160 added to the dispersion in the XTEMP-R to make a final volume that coincided with the 15-mL . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 161 mark on the device and a final concentration of 40 mg/mL. The device was capped and shaken 162 25 times to mix thoroughly. For redispersion, the suspension was shaken 25 times. 163 Evaluation of suspensions prepared in XTEMP-R 164 Visual observation 165 TBAJ-876 and TBI-223 166 The prepared suspensions of TBAJ-876 and of TBI-223 were shaken, and then an aliquot of each 167 was poured onto a watch glass. The suspensions were examined for color, uniformity, and 168 presence of large particles, agglomerates, or clumps. 169 Fineness of dispersion 170 Dispersions of tablets in water prepared in the XTEMP-R device were tested for fineness of 171 dispersion. 172 TBAJ-876 and TBI-223 173 One tablet was added to the XTEMP-R followed by 5 mL of water. The tablet was allowed to 174 soak for 5 minutes, followed by 2 minutes of massaging in the XTEMP-R. The dispersion was 175 poured through a #18 sieve (1000 µm opening) with a pan at the bottom for collecting the 176 dispersion. This test was performed in triplicate by each of two analysts. 177 Total dose recovery from tablet dispersion in XTEMP-R 178 TBAJ-876 179 The prepared 25 mL suspension in the XTEMP-R device was shaken 25 times and transferred to 180 a 250 mL volumetric flask. The device was rinsed with 15 mL of water and the rinse was added 181 to the volumetric flask with the suspension. This stock solution was diluted to volume with 1:1 182 acetonitrile:water. A sample of this stock solution was further diluted with diluent (Table 1) to a . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 183 concentration of 0.04 mg/mL. An aliquot of this diluted sample was filtered and analyzed by 184 HPLC as described under Analytical test methods below. The recovery was tested on three 185 preparations. 186 TBI-223 187 The prepared 15 mL suspension in the XTEMP-R device was shaken 25 times and transferred to 188 a 250 mL volumetric flask. The device was rinsed with 15 mL of water and the rinse was added 189 to the volumetric flask with the suspension. A volume of 30 mL of acetonitrile was added to the 190 flask and mixed. This stock solution was diluted with diluent (Table 1) to volume. A sample of 191 this stock was further diluted with diluent to a concentration of 0.05 mg/mL. An aliquot of this 192 sample was filtered and analyzed by HPLC as described under Analytical test methods below. 193 The recovery was tested on three preparations. 194 Dose reproducibility of aliquots of tablet dispersion in XTEMP-R 195 A general technique for withdrawal of aliquots for partial doses is represented in Fig 3. 196 Fig 3. Withdrawal of an Aliquot from XTEMP-R for Partial Dose of TBI-223 Suspension. 197 198 TBAJ-876 199 Prior to withdrawal of the dose aliquot, a syringe adapter was attached to the opening of 200 XTEMP-R and the device was capped. The prepared 25 mL suspension in the XTEMP-R device 201 was shaken 25 times and a 3-mL oral syringe was attached to the syringe adapter. A 2-mL 202 aliquot was removed for an 8-mg dose. The dose reproducibility was tested on three 2-mL 203 aliquots withdrawn from the same preparation. For each withdrawal of the aliquot, the capped 204 device was shaken to simulate the procedure that would be followed by the patient or . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 205 caregiver. This was repeated on three different preparations. Each 8-mg dose was diluted with 206 diluent to a concentration of 0.04 mg/mL, filtered, and analyzed by HPLC. The remaining 207 suspension in the XTEMP-R was left undisturbed on the bench for about 24 hours. The 208 preparations were redispersed by shaking and one aliquot from each preparation was 209 withdrawn and tested. 210 TBI-223 211 Prior to withdrawal of the dose aliquot, a syringe adapter was fitted on to the device and the 212 device was capped. The prepared 15 mL suspension in the XTEMP-R device was shaken 25 213 times and a 3-mL oral syringe was attached to the syringe adapter. A 2-mL aliquot was removed 214 for an 80-mg dose. The dose reproducibility was tested on three 2-mL aliquots withdrawn from 215 the same preparation. For each withdrawal of the aliquot, the capped device was shaken to 216 simulate the procedure that would be followed by the patient or caregiver. This was repeated 217 on three different preparations. Each dose withdrawn was transferred into a 100-mL volumetric 218 flask. Acetonitrile 2 mL was added to the flask and swirled to mix the sample with the solvent. 219 The mixture in the flask was then diluted with diluent to volume. An aliquot of 3 mL of this 220 stock sample preparation was diluted to 50 mL to a concentration of 0.05 mg/mL. An aliquot of 221 this sample preparation was filtered and analyzed by HPLC. The remaining suspensions in the 222 XTEMP-R were left undisturbed on the bench for about 24 hours and an aliquot from each 223 preparation was tested after redispersing. 224 Analytical test methods for TBAJ-876 and TBI-223 225 Stability-indicating validated HPLC methods were used for the potency testing of TBI-223 and 226 TBAJ-876 suspensions. Details of the HPLC methods are provided in Table 1. . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 227 Table 1. Details of Stability-Indicating HPLC Methods for Potency Testing of TBI-223 and TBAJ- 228 876 Suspensions. Details Parameter TBI-223 TBAJ-876 Instrument Hitachi L-2100 pump, Shimadzu SPD-10AVP detector, Shimadzu SCL-10AVP controller, Shimadzu CTO-AVP column heater, SRI Instruments PeakSimple chromatography data system Column Zorbax Bonus RP (C18, 4.6 mm x 150 mm, 3.5μm) Waters Symmetry Shield RP-8 (4.6 mm x 150 mm, 5μm) Wavelength 258 nm 236 nm Column Temp. 30 °C 40 °C Flow Rate 0.8 mL/min 2.0 mL/min Injection Volume 10 µL 5 µL Syringe filter 1.0 µm glass fiber filter 0.45 µm PVDF syringe filter Standard and sample Concentration 0.05 mg/mL 0.04 mg/mL Mobile Phase Mobile Phase-A: 0.05% TFA in water Mobile Phase-B: 0.05% TFA in Acetonitrile 0.01M Ammonium acetate: Acetonitrile (1:3) Diluent 0.2% SLS in Water:Acetonitrile (1:1) Water:Acetonitrile (1:4) Run Time 8 minutes (Gradient: 0.0-2.0 mins: A:64% and B:36%; 2.0-4.5 mins: A:64% and B:36% to A:46% and B:54%; 4.6-8.0 mins: A:64% and B:36%) 7 minutes (Isocratic) Peak retention time About 3.6 minutes About 4.4 minutes Integration Peak area method using PeakSimple data acquisition system Peak area method using PeakSimple data acquisition system 229 230 TBAJ-876 quantification method validation 231 The method was validated for specificity (placebo interference and forced degradation), 232 linearity, filter study, precision (system suitability and repeatability), and accuracy according to 233 International Conference on Harmonization (ICH) guidelines [10]. Specificity was assessed to 234 verify the absence of interference from tablet excipients, and suspension matrix and to . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 235 establish the analyte peak does not interfere with the possible degradants of the forced 236 degradation of samples. Seven-point calibration curve was constructed with standard solutions 237 in the range of 50% (20 μg/mL) to 150% (60 μg/mL) of standard concentration i.e., 40 μg/mL. 238 TBI-223 quantification method validation 239 The method was validated for specificity (placebo interference and forced degradation), 240 linearity, filter study, precision (system suitability and repeatability), and accuracy according to 241 ICH guidelines. Specificity was assessed to verify the absence of interference from tablet 242 excipients, and suspension matrix and to establish the analyte peak does not interfere with the 243 possible degradants of the forced degradation of samples. Five-point calibration curve was 244 constructed with standard solutions in the range of 50% (25 μg/mL) to 150% (75 μg/mL) of 245 standard concentration i.e., 50 μg/mL. 246 Dispersions of commercial tablets prepared in XTEMP-R 247 We tested five different commercially available tablets to determine effectiveness of the 248 XTEMP-R device in producing a fine dispersion that passed through a #18 sieve (1000 um 249 opening). The commercial tablets were selected to represent small and large tablets. 250 Manufacturer details, composition, tablet weight and drug content of the commercial tablets 251 tested are provided in Table 2. Metformin tablets were included for evaluation to challenge the 252 dispersing functionality of the XTEMP-R device, as they represent high dose, and high drug load 253 tablets with a high drug to excipient ratio. . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 254 We tested the dispersibility of these commercial tablets by using the same methodology of 255 soaking them in water for 5 minutes and massaging for 2 minutes, similar to the TBAJ-876 and 256 TBI-223 tablets. The suspensions were tested for fineness of dispersion. 257 We also tested these commercial tablets for the shortest massaging time that could accomplish 258 dispersion for fineness. One tablet was added to the XTEMP-R followed by 5 mL of water and 259 massaged in the XTEMP-R device until the analyst felt that the tablet was completely dispersed, 260 and the time was recorded. The suspension was poured through a #18 sieve (1000 µm opening) 261 with a pan at the bottom for collecting the dispersion. This test was performed in triplicate by 262 each of two analysts. . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 263 264 Table 2. Commercial Tablets Tested for Dispersion Times for Fineness of Dispersion. Product Manufacturer NDC Inactive Ingredients Tablet Weight (mg) % Drug in Tablet Valsartan 320 mg MacLeods 33342-065-10 Colloidal silicon dioxide, crospovidone*, hypromellose, iron oxides (yellow, black and/or red), microcrystalline cellulose, magnesium stearate, polyethylene glycol, talc and titanium dioxide 1030 31.1 Acetaminophen 500 mg (Tylenol®) McNeil 50580-449-96 Carnauba wax, corn starch, FD&C red no. 40 aluminum lake, hypromellose, magnesium stearate, modified starch, polyethylene glycol, powdered cellulose, pregelatinized starch, propylene glycol, shellac, sodium starch glycolate*, titanium dioxide 610 82.0 Glimepiride 2 mg Accord 16729-002-01 Lactose monohydrate, sodium starch glycolate*, povidone, and magnesium stearate. Ferric oxide yellow and FD &C blue #2 aluminum lake 170 1.2 Amlodipine 2.5 mg Ascend 67877-197-90 Microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate*, colloidal silicon dioxide and magnesium stearate 100 2.5 Metformin 1000 mg Ascend 67877-563-01 Povidone (K-30), povidone (K-90), pregelatinized starch*, and magnesium stearate. Coating: artificial blackberry flavor, hypromellose and polyethylene glycol. 1080 92.6 265 *disintegrant . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 266 Results 267 Preparation of suspensions from tablets using XTEMP-R 268 TBAJ-876 and TBI-223 269 The suspension preparation technique for the two tablets, TBAJ-876 and TBI-223, was found to 270 be simple, efficient and could be performed well in this closed system. The suspensions were 271 prepared in less than 10 minutes without any complicated, tedious, or messy steps. The details 272 of the suspension evaluation are provided below. 273 Evaluation of suspensions prepared in XTEMP-R 274 Visual observation 275 TBAJ-876 and TBI-223 276 Fig 4 shows the visual appearance of the suspensions of the two drugs, TBI-223 and TBAJ-876. 277 Both suspensions had uniform appearance and the particles were observed to be 278 homogeneously dispersed. TBI-223 suspension was observed to be milky white, opaque, and 279 uniform when light was shown from below the watch glass containing the suspension. TBAJ-876 280 suspension was translucent with distinct particles visible and uniformly dispersed. The 281 appearance of the suspension as translucent or opaque is dependent on the ingredients and 282 composition of the tablets and the dispersion vehicle. 283 Fig 4. Visual Observation of Suspensions Prepared in XTEMP-R. (a) Appearance of TBAJ-876 284 suspension, (b) TBAJ-876 suspension in XTEMP-R device, (c) Appearance of TBI-223 suspension, 285 (d) TBI-223 suspension in XTEMP-R device. 286 287 Fineness of dispersion 288 TBAJ-876 and TBI-223 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 289 The dispersions prepared with 5-minute soaking and 2-minute massaging times in the XTEMP-R 290 device passed through the #18 sieve. No particles were retained indicating that all particles 291 were below 1000 µm and dispersed particles were not forming aggregates or agglomerates. 292 Total dose recovery from tablet dispersion in XTEMP-R 293 TBAJ-876 and TBI-223 294 The total dose recovered from the triplicate preparations of TBAJ-876 and TBI-223 in XTEMP-R 295 are presented in Table 3. The recovery of TBAJ-876 from three distinct preparations in XTEMP-R 296 ranged from 98.8-100.0% with an average recovery of 99.2%. The recovery of TBI-223 from 297 three distinct preparations in XTEMP-R ranged from 100.4-102.9% with an average recovery of 298 101.3%. These ranges include inherent tablet-to-tablet content variability as well as analytical 299 variability. 300 301 Table 3. Recovery of TBI-223 and TBAJ-876 from Suspensions Prepared in XTEMP-R. Tablet Suspending Agent Dispersion time (minutes) Preparation Total Recovered (%) from entire contents in device 1 98.8 2 100.0 3 99.0TBAJ-876 Water + ORA- Sweet 5 minutes soak+2 minutes massage Average (RSD) 99.2 (0.64) 1 100.4 2 100.5 3 102.9TBI-223 Water + ORA- Blend 5 minutes soak+2 minutes massage Average (RSD) 101.3 (1.4) 302 RSD = relative standard deviation 303 Dose reproducibility of aliquots of tablet dispersion in XTEMP-R 304 TBAJ-876 and TBI-223 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 305 The results for dose reproducibility are provided in Table 4. Average potency of three 306 suspensions from three replicate aliquots of 2-mL from each suspension were found to be 307 98.9-99.7% for TBI-223 suspensions, and 102.6-103.2% for TBAJ-876 suspensions. The potency 308 of an additional aliquot withdrawn after redispersing after 24 hours from each of the three 309 suspensions was found to be 96.0-100.3% for TBAJ-876 suspensions and 99.3-100.3% for 310 TBI-223 suspensions. . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 311 312 Table 4. Dose Reproducibility of Aliquots Withdrawn from TBAJ-876 and TBI-223 Suspensions. Theoretical dose dispensed (%)Tablet Suspending Agent Aliquot Preparation 1 Preparation 2 Preparation 3 TBAJ-876 Water + ORA-Sweet 99.2 101.2 102.2 104.5 102.5 104.3 Day 0 105.7 104.2 103.0 Average (RSD) 103.1 (3.44) 102.6 (1.44) 103.2 (0.99) Day 1 96.0 100.3 98.2 TBI-223 Water + ORA-Blend 99.4 98.8 99.9 98.5 98.9 99.8 Day 0 99.3 98.9 99.5 Average (RSD) 99.1 (0.5) 98.9 (0.1) 99.7 (0.2) Day 1 100.3 99.3 100.2 313 RSD = relative standard deviation . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 314 TBAJ-876 tablets test method validation 315 The seven-point calibration curve in the range of 20 μg/mL to 60 μg/mL was linear with a high 316 correlation coefficient (r) of 1.000. For both standard and sample tests, % RSD for inter- and 317 intra-day precision were well below 2%, and mean recovery was well within the range of 98% to 318 102%. 319 TBI-223 tablets test method validation 320 The five-point calibration curve in the range of 25 μg/mL to 75 μg/mL was linear with a high 321 correlation coefficient (r) of 1.000. For both standard and sample tests, % RSD for precision 322 were well below 2%, and mean recovery was well within the range of 98% to 102%. 323 Dispersions of commercial tablets prepared in XTEMP-R 324 The suspensions prepared with 5-minute soaking and 2-minute massaging times in the 325 XTEMP-R device passed through the #18 sieve. No particles were retained indicating that all 326 particles were below 1000 µm and dispersed particles were not forming aggregates or 327 agglomerates. 328 The earliest dispersion times for all commercial tablets tested ranged from 1-3 minutes except 329 for metformin which did not disintegrate within the time tested (10 minutes soaking and 5 330 minutes massaging). The dispersion times presented in Table 5 represent the dispersion time 331 for the suspensions prepared by two independent analysts that passed the fineness of 332 dispersion test. 333 The drug content (labelled dose of the drug in total tablet weight) and disintegrant in each 334 tablet formulation are provided in Table 2. Except for metformin, all other tablet formulations . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 335 contained superdisintegrants. Valsartan, acetaminophen, and metformin had 31, 82, and 93% 336 of drug load, respectively. Glimepiride and amlodipine contained 1.2 and 2.5% of drug load, 337 respectively. 338 Table 5. Dispersion Times of Commercial Tablets. Tablet Dispersion Time (min) in X-TEMP-R Valsartan 1.5 Acetaminophen 3 Glimepiride 3 Amlodipine 1 Metformin >10* 339 *Did not disperse in time tested (10 minutes soaking and 5-minute massaging) 340 Discussion 341 Tablet splitting, crushing, and grinding is a common practice for medication administration. The 342 necessity for splitting or crushing tablets arises from the need to administer drug doses other 343 than that are available in tablet formulations, as well as facilitate the swallowing of tablets [11]. 344 There have been some challenges identified with both, tablet splitting and tablet pulverization. 345 Large deviations of dose can occur due to unequal fragments of split tablets or weight 346 differences due to loss of powdered or chipped material resulting from the splitting process [9]. 347 Tablet crushing can result in significant drug loss [5]. Some crushing devices yield large particles 348 that cannot be administered via a feeding tube [4]. Aerosolized powder during crushing and 349 grinding can be an environmental [2] and health hazard. 350 This paper describes a procedure for converting tablets into a suspension: (1) that is simple and 351 reproducible; (2) where tablet disintegration and preparation of suspension is performed within . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 352 the same device; (3) in a contained environment; (4) that enables measurement and 353 withdrawal of any required dose with accuracy; (5) with small particle size that permits 354 administration through feeding tubes; and (6) where consumption is possible from the same 355 receptacle. 356 XTEMP-R is a simple mechanical device designed to facilitate and expedite the disintegration 357 and dispersion of tablets in a small volume (<10 mL) of water. This device is constructed with 358 low hardness silicone, making it pliable yet durable. It can be gently squeezed by fingers to 359 facilitate the dispersion of the tablet. This squeezing and massaging action facilitated the 360 interaction of water with the superdisintegrants present in the tablet, thus promoting its 361 dispersion. These ingredients are routinely included in the tablet formulations to aid in the 362 break-up of the compacted mass. 363 The disintegration and suspension of tablets in the XTEMP-R device occurs in the same 364 container in a closed environment. Therefore, there is minimal risk of any drug loss during the 365 preparation. The XTEMP-R container does not have any cutting or grinding parts. It is also safer 366 for caregivers to prepare the suspension with XTEMP-R since there is minimal contact with the 367 drug either by touch or by inhalation of drug powder that may get aerosolized during 368 pulverization. 369 Both TBAJ-876 and TBI-223 tablets are investigational drugs under IND applications with 370 established specifications and content uniformity standards. As demonstrated by the results, 371 TBAJ-876 and TBI-223 tablets could be dispersed homogenously in water and suspending 372 vehicle within 10 minutes. Accurate aliquots could be withdrawn reproducibly from the device . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 373 immediately after the preparation and 24 hours later. We withdrew aliquots from each 374 preparation sequentially after preparation and on the following day after redispersing by 375 shaking. This closely simulates what would occur in the pharmacy, at the patient’s home or at 376 the clinical investigation site. The partial doses withdrawn for the suspension were uniform and 377 stable as they could be redispersed reproducibly after 24 hours. It was not our intent to 378 prepare suspensions for long term storage. 379 Fineness of dispersion was one of the quality criteria. The suspensions were tested by passing 380 them through a #18 sieve (1000 µm aperture). Our objective was to ensure that no particle 381 agglomerates were present in the suspension and that the largest particles in the suspension 382 could be suspended in commonly available suspending vehicles. Bowles and colleagues [13] 383 have demonstrated that particles up to 1000 µm can be successfully suspended with the aid of 384 commonly used suspending vehicles. 385 Drug loss is one of the challenges when the tablets are pulverized before dispersing in a 386 suspension. Drug powder tend to stick to the walls of the container such as a mortar and pestle. 387 Thong and colleagues [5] have recommended two rinses of the tablet crushing devices to 388 ensure minimum drug loss. Close to 100% of active drug from all three suspensions of TBAJ-876 389 and TBI-223 prepared by the XTEMP-R device was recovered. The devices were only rinsed once 390 with 15 mL of water for each preparation. The total dose could be ingested directly from the 391 device avoiding a transfer to a dispensing container. This methodology offers an alternative 392 dose administration option for patients suffering from dysphagia. . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 393 We have also investigated the applicability of this device for some commercial tablets. Except 394 for metformin, the tablets could be dispersed by soaking for 5 minutes and massaging for 2 395 minutes. For some products, the dispersion could be faster by just massaging for 1-3 minutes. 396 The metformin tablets had a high drug load with just about 8% excipients and did not contain 397 any superdisintegrants. Desai and colleagues [14] studied metformin formulation with minimal 398 excipients and concluded that even for a highly soluble drug, a superdisintegrant was needed in 399 the formulation to change the dissolution mechanism from erosion-diffusion to disintegration. 400 Masum and colleagues [15] formulated metformin tablets with different disintegrants and 401 found that the wetting time, dispersion time and the disintegration time of metformin tablets 402 were governed by the type and quantity of the superdisintegrants. In the XTEMP-R device, the 403 volume of the dispersing vehicle (5-7 mL water) and massaging are not sufficient to have 404 effective erosion-diffusion for the tablet to dissolve or disperse the metformin tablet. 405 Therefore, the use of the XTEMP-R device may be limited for tablets that depend primarily on 406 solubilization for dissolution and do not contain effective disintegrants. These observations 407 corroborate our assumption that XTEMP-R promotes the interaction between water and tablet 408 formulations. The ingredients of each tablet formulation can be found in the product 409 prescribing information. 410 The lack of child-friendly formulations leaves 40% of the world population at increased risk for 411 preventable adverse events, suboptimal dosing, noncompliance, and lack of access to new 412 medicines [16]. In some instances, the caregiver is required to administer a quarter of a tablet 413 to a neonate. XTEMP-R device may offer an alternative for accurate dosing in this patient 414 population. Of course, appropriate development and analytical work will have to be performed. . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 415 Fortunately, several publications [17,18] describing the compatibility of drugs that lack pediatric 416 formulations with commonly available suspending agents and with established storage 417 conditions and shelf life are available. 418 Limitations 419 XTEMP-R device worked well with the tablets containing superdisintegrants in the formulation. 420 This device, however, may not work well with certain large tablets with a high drug-to-excipient 421 ratio and/or tablets not containing effective disintegrants in the formulation. This will have to 422 be tested on a case-by-case basis. 423 This device does not offer protection from light. Photosensitive drug preparations should be 424 stored in the device with added protection from light. 425 The silicone material of the XTEMP-R device may be stained from a colored drug dispersion. 426 Therefore, it is recommended that a dedicated device should be used for colored drugs such as 427 clofazimine. 428 Dose preparation may be challenging for patients that are unable to massage the tablet in the 429 device. XTEMP-ETM, another version of XTEMP-R is equipped with an electronic mechanism for 430 mixing. XTEMP-E will be presented in a subsequent publication. 431 The utility of this device and methodology for suspending any tablet formulation has to be 432 supported by appropriate development and analytical work. As exemplified by the work 433 conducted for TBAJ-876 and TBI-223 in this paper, similar rigor is recommended for any other 434 drug that will utilize XTEMP-R for suspension. . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 435 Conclusion 436 We have demonstrated that the new XTEMP-R device can be utilized for aliquoting partial 437 doses of TBAJ-876 and TBI-223 immediate release tablets. Homogeneous suspensions could be 438 prepared conveniently, safely, and expeditiously without any significant loss. Further, this 439 device has the potential to offer an alternative for dosing patients who cannot ingest 440 immediate release tablets. This could be beneficial to pediatric and elderly patients, intubated 441 patients, and patients with dysphagia. Additional work is required to establish the utility of the 442 device for other immediate release tablets. 443 Acknowledgements 444 The authors are grateful for the funding provided by TB Alliance. 445 References 446 1. Ranked: The most prescribed drugs in the U.S. by Omri Wallach, Graphics/Design: 447 Amy Realey; 2021 Nov 1; https://www.visualcapitalist.com/ranked-the-most- 448 prescribed-drugs-in-the-u-s/. (accessed 2021 Dec 12). 449 2. Damien Salmon, Elisa Pont, Hélène Chevallard, Elhadji Diouf, Mamadou-Lamine Tall, 450 Christine Pivot, Fabrice Pirot, Pharmaceutical and safety considerations of tablet 451 crushing in patients undergoing enteral intubation, International Journal of 452 Pharmaceutics, Volume 443, Issues 1–2, 2013, Pages 146-153, ISSN 0378-5173, 453 https://doi.org/10.1016/j.ijpharm.2012.12.038. 454 3. 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CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 508 16. Milne CP, Bruss JB. The economics of pediatric formulation development for off- 509 patent drugs. Clin Ther. 2008 Nov;30(11):2133-45. doi: 510 10.1016/j.clinthera.2008.11.019. PMID: 19108801. 511 17. Jew RK, Soo-Hoo W, Erush SC, et al. Extemporaneous formulations for pediatric, 512 geriatric, and special needs patients, 3rd ed. ASHP, 2016. 513 18. Nahata, MC, Pai, VB. Pediatric drug formulations, 7th ed. Harvey Whitney Books 514 Company, 2018. . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint 516 Supporting Information 517 Link to video for suspension preparation methodology 518 https://www.dropbox.com/sh/t0bj2o6ivjuh8l3/AAAZe3mRxc1HImGlbpoFDUUua?dl=0 519 S1 Fig. Representative chromatograms of TBAJ-876 analysis (a) Standard 1, (b) Diluent blank, 520 (c) Day 0 aliquot for dose reproducibility, (d) Day 0 suspension matrix blank (diluent + ORA- 521 Sweet), (e) Day 1 aliquot for dose reproducibility, (f) Day 1 suspension matrix blank (diluent + 522 ORA-Sweet), (g) Standard 2, (h) Total dose recovery 523 S2 Fig. Representative chromatograms of TBI-223 analysis (a) Standard 1, (b) Diluent blank, (c) 524 Day 0 aliquot for dose reproducibility, (d) Day 0 suspension matrix blank (diluent + ORA-Blend), 525 (e) Day 1 aliquot for dose reproducibility, (f) Day 1 suspension matrix blank (diluent + ORA- 526 Blend), (g) Standard 2, (h) Total dose recovery 527 . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint Author contributions Rajneesh Taneja conceptualized and designed the device and experiments Joseph Scarim conceptualized and designed the device and experiments Poonam G Pande designed and coordinated the testing, corresponding author Anthony Scarim conducted the analytical work Milap C Nahata consulted on the utility of the device Rita K Jew consulted on the utility of the device Koteswara Inabathina coordinated the device manufacture . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint . CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 30, 2022. ; https://doi.org/10.1101/2022.08.26.22279282doi: medRxiv preprint