Solid-state transformation of different gabapentin polymorphs upon milling and co-milling

• Published in: International journal of pharmaceutics Vol. 396; no. 1; pp. 83 - 90
• Main Authors: Lin, Shan-Yang, Hsu, Cheng-Hung, Ke, Wen-Ting
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 30.08.2010; Elsevier
• Subjects: Additives; Amines - chemistry; Analgesics - chemistry; Anticonvulsants - chemistry; Biological and medical sciences; Chemistry, Pharmaceutical; Co-milling; Crystallization; Cyclohexanecarboxylic Acids - chemistry; Drug Stability; Excipients - chemistry; Gabapentin; gamma-Aminobutyric Acid - chemistry; General pharmacology; Medical sciences; Microspectrophotometry; Milling; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polymorphic transition; Spectroscopy, Fourier Transform Infrared; Technology, Pharmaceutical - methods; Time Factors; Water - chemistry; Polymorphic transition; Additives; Gabapentin; Milling; Co-milling; Pharmaceutical technology; Grinding(comminution); Anticonvulsant; Polymorphic transformation; Solid state; Additive; Analgesic; Polymorphism
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2010.06.014

The purpose of this study was to investigate the milling effect on the polymorphic transformation of four gabapentin (GBP) Forms I–IV in the absence of additive. Four polymorphs of GBP were previously prepared and identified, in which the GBP Form I was proven to be a monohydrate, but other GBP Forms II–IV belonged to anhydrate. The GBP Form II was the most stable polymorph available in the market. The co-milling process affecting the polymorphic stability of GBP Form II with different additives was also examined. During the 120-min-milling or co-milling course, the milled sample was withdrawn at prescribed intervals for Fourier transform infrared (FTIR) microspectroscopic determination. In the absence of additive, each polymorph of GBP exhibits a different polymorphic transformation behavior in the 120-min-milling course. The results indicate that GBP Form I was previously dehydrated and transited to Form II; GBP Form II was first transformed to Form III and then changed to Form IV; GBP Form III was previously transited to Form II, then changed to Form III and transformed to Form IV at last; whereas GBP Form IV was first changed to Form II, then transited to Form III and finally to Form IV. It was clearly evidenced that if GBP Form III or IV appeared in the milled mixture a little amount of GBP-lactam was certainly detected. In the presence of additives, there was almost lack of polymorphic transition for GBP Form II by co-milling GBP Form II with Emcompress, β-cyclodextrin, mannitol, corn starch or magnesium stearate. By co-milling GBP Form II with Avicel, dextrin, hydroxypropyl β-cyclodextrin, hydroxypropyl methylcellulose, Kollidon K-30 or gelatin, GBP Form II was transformed to Form IV alone. On the other hand, the GBP Form IV and a little amount of GBP-lactam were also found in the co-milled mixture after co-milling with GBP Form II with Aerosil or talc. This reveals that the solid-state transformation of GBP Form II after co-milling was markedly dependent on the types of additive used.