Issue link: https://www.e-digitaleditions.com/i/238663
c-Kheurart_10-15_Masters 12/30/13 1:55 PM Page 14 Tablets & Capsules 14 January 2014 (BHT) were added as preservatives. Accelerated stability studies were then conducted on all formulations to determine the shelf-life of each drug product. The manufacturing process involved melting the excipients at a temperature of ~65°C and then dispersing the API into each mixture by stirring. The molten mixtures were then placed into hard gelatin capsules (Licaps from Capsugel). Lots 5 and 6 were manufactured by dissolving the API into excipient preparations 27F and 27H, respectively. Results and discussion Stage 1: Vehicle screening studies. None of the individual excipients subjected to the screening studies achieved the target solubility (~200 mg/mL) at both ambient and elevated temperatures. Table 4 lists which excipients displayed 1) insolubility and partial wetting properties and which were 2) partially soluble at elevated temperatures. The excipients that were screened but not listed in the table were observed to have neither wetting nor solubilization properties. Stage 2: Mixture approach to solubility studies at elevated temperatures. The API was partially soluble in mixtures 1 to 11, 14, 17, 18, 20, 21, 22, 24, and 25, as numbered in Table 2. None of the mixtures, however, could obtain the target solubility of ~200 mg/mL. Stage 3: Selection of optimal mixture. The in vitro dissolution rates in 0.1 N HCl of all six excipient mixtures used to formulate the LFHC prototypes are shown in Table 5 and Figure 1. Note that the initial dissolution of Lot 2 and Lot 4 was slower (13 percent after 10 minutes) than those of the other prototypes (>65 percent). The different results can be attributed to the different properties of the excipients and the different ratios of excipients that were used. Overall, the dissolution profiles provide a reasonable spread of prototype formulations for conducting in vivo animal studies. Although a clear solution was not obtained, Lot 1 and Lot 3 dissolved 75 percent of the API in 45 minutes, which justifies further evaluation of both prototype formulations in animal studies. No significant changes in the appearance of the capsule shell and the contents of the capsule were noted during accelerated stability studies. Chemical stability was also encouraging. Finally, no leakage of the contents was observed, even though the capsules were not sealed. Figures 2 and 3 show the accelerated stability data for lots 1 and 3. Excipient preparations 27F and 27H (lots 5 and 6) were not considered for further assessment. They will only be re-evaluated if required, based on the results of the in vivo studies conducted using lots 1 and 3. Table 3 Mixtures used to evaluate in vitro dissolution (milligrams per capsule) Gelucire 44/14 Lot 1 Lot 2 Lot 3 Lot 4 Imwitor 308 Vitamin E TPGS HPBCD Propylene glycol BHA BHT 248.59 498.59 -348.59 250 -248.59 125.00 --200 -- ---25 -- 0.1 0.1 0.1 0.1 0.5 0.5 0.5 0.5 50 -- Table 4 Observations during solubility studies at elevated temperature Insoluble with partial wetting properties Partially soluble Gelucire 44/14, Gelucire 50/13, Polysorbate 80, S.E.L.F. 27F, and S.E.L.F. 27H Propylene glycol, Miglyol 810, Imwitor 308, Imwitor 988, Crillet 1 HP, Solutol HS 15, glycerin, Capryol 90, Imwitor 491, Imwitor 742, Labrasol, Cremophor RH 40, MCT, Capmul MCM, and hexylene glycol. Table 5 In vitro dissolution of selected mixtures in 0.1 N HCl (mean percentage dissolved) 10 min Lot 1 Lot 2 Lot 3 Lot 4 S.E.L.F. 27F (Lot 5) S.E.L.F. 27H (Lot 6) 20 min 30 min 45 min 60 min Infinity 66 13 83 13 68 80 102 34 95 43 84 91 103 48 99 78 89 93 104 70 101 97 90 93 104 85 102 100 91 93 104 102 103 101 91 93