Changes in Drug Release Rate from Polymeric Matrix Dosage Forms Including Microspheres

Polymeric matrix dosage forms intended for controlled release may undergo changes in drug release rate upon storage. For example, poly(d,/-lactic acid) microspheres exhibited shrinkage and decreased release rates of phenobarbitone after 6-month storage at 37°C.711 Various physical properties of the matrix such as the glass-transition temperature ( Ts) and the crystalline states of polymers affect drug release from polymeric matrix dosage forms. Changes in these properties during storage can lead to changes in the drug release rate.

4 10 20 25 30 storage temperature (°C)

Figure 176. Effect of storage temperature on the charge in melting time of suppositories following 6-month storage. (Reproduced from Ref. 707 with permission.)

4 10 20 25 30 storage temperature (°C)

Figure 176. Effect of storage temperature on the charge in melting time of suppositories following 6-month storage. (Reproduced from Ref. 707 with permission.)

temperature (°C)

temperature (°C)

Figure 177. DSC curves showing polymorphic phase transitions of a triglyceride on storage. (a) Before storage; (b) after 6-month storage at 25°C. (Reproduced from Ref. 709 with permission.)

An increase in the Ts of poly(d, /-lactide-co-glycolide) microspheres was observed during storage at 40°C.712 The Tr of biodegradable microspheres may also decrease as a result of polymer decomposition during storage. The lowered Tr of poly(Mactide) micro-spheres due to the lowered molecular weight of the polymer resulted in an increase in drug release rate from the microspheres.713 Particularly important may be the acceleration of hydrolysis in matrices containing basic drug substances.714

Changes in the crystalline state of polymer matrices during storage may result in changes in drug release from microspheres. Amorphous poly( /-lactide) microspheres containing progesterone exhibited an increased release rate following storage due to polymer crystallization (Fig. 179).713715 Storage at temperatures above the Tr increased crystallization, as shown by a diminished exothermic peak in the DSC thermogram recorded following storage, compared to that of a fresh sample (Fig. 180). It was suggested that drug

0 6 12 18 24 30 36 storage time (month)

0 6 12 18 24 30 36 storage time (month)

Figure 178. Changes in the dropping points (the temperature required for suppositories to melt and fall from a grease cup orifice) of suppositories following storage at 15°C (•) or 25°C (■) and 75% RH. (Reproduced from Ref. 710 with permission.)

Figure 179. Changes in drug release rate due to crystallization upon storage. Drug release rates were measured before storage (O), after 7-month storage at 30°C and 0% RH (V), at 30°C and 50% RH (•), and at 30°C and 75% RH (▲), and after 6-month storage at 50°C and 0% RH (D)and at 50°C and 11% RH (■). (Reproduced from Ref. 713 With permission.)

Figure 179. Changes in drug release rate due to crystallization upon storage. Drug release rates were measured before storage (O), after 7-month storage at 30°C and 0% RH (V), at 30°C and 50% RH (•), and at 30°C and 75% RH (▲), and after 6-month storage at 50°C and 0% RH (D)and at 50°C and 11% RH (■). (Reproduced from Ref. 713 With permission.)

distribution within the microspheres changed with crystallization, resulting in the increased release rate.713715 It was proposed that increased crystallization might have occurred even at temperatures below the Tg in the presence of increased humidity, thereby lowering the Ts through polymer hydrolysis.

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