Comparative effects of some hydrophilic excipients on the rate of gabapentin and baclofen lactamization in lyophilized formulations.
The aim of this study was to gain insights into the role played by some excipients on the stability of gabapentin 1 and baclofen 2 which can undergo degradation giving rise to the corresponding lactams 2-azaspiro[4.5]decan-3-one 3 and 4-(4-chlorophenyl)-2-pyrrolidone 4, respectively. A screening study was carried out on drug and drug-excipient freeze-dried mixtures at 50 degrees C and under three different humidity values by using a number of commonly available excipients. These include hydroxypropyl-beta-(HP-beta-CD), sulfobutyl-beta-cyclodextrin (SBE-beta-CD), lactose, raffinose, trehalose, PVP-K30 and mannitol. For most cases, it was found that the lactam formation can be satisfactory described by an apparent zero-order equation. Excipients shown to negatively impact gabapentin stability are HP-beta-CD, SBE-beta-CD, lactose and PVP K30 while only this last excipient had a significant effect on the degradation of baclofen. The results can be rationalized in terms of conformational factors favouring the intramolecular dehydration reaction. A positive effect of moisture on the lactamization process was observed under some circumstances. Water may provide a favourable environment for degradation. These findings, taken together, should be considered during the selection of excipients for a possible formulation of gabapentin and baclofen.
Cutrignelli
Annalisa
A
Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università degli Studi di Bari, Via Orabona 4, 70125 Bari, Italy.
Denora
Nunzio
N
Lopedota
Angela
A
Trapani
Adriana
A
Laquintana
Valentino
V
Latrofa
Andrea
A
Trapani
Giuseppe
G
Liso
Gaetano
G
D000588:Amines / Q000737:chemistry*; D000927:Anticonvulsants / Q000737:chemistry*; D001418:Baclofen / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D003509:Cyclohexanecarboxylic Acids / Q000737:chemistry*; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry*; D005612:Freeze Drying; D000077206:Gabapentin; D006813:Humidity; D007700:Kinetics; D007769:Lactams / Q000737:chemistry*; D007785:Lactose / Q000737:chemistry; D008353:Mannitol / Q000737:chemistry; D008956:Models, Chemical; D015394:Molecular Structure; D010276:Parasympatholytics / Q000737:chemistry*; D011205:Povidone / Q000737:chemistry; D011887:Raffinose / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods; D013696:Temperature; D013818:Thermogravimetry; D014199:Trehalose / Q000737:chemistry; D014867:Water / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000737:chemistry; D005680:gamma-Aminobutyric Acid / Q000737:chemistry*
D000588:Amines; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D005079:Excipients; D007769:Lactams; D010276:Parasympatholytics; D047392:beta-Cyclodextrins; D014867:Water; D008353:Mannitol; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D014199:Trehalose; D011205:Povidone; D001418:Baclofen; D007785:Lactose; D011887:Raffinose