title: Comparative effects of some hydrophilic excipients on the rate of gabapentin and baclofen lactamization in lyophilized formulations.
abstract: 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.
authors.affiliation: Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università degli Studi di Bari, Via Orabona 4, 70125 Bari, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Cutrignelli
authors.forename: Nunzio
authors.initials: N
authors.lastname: Denora
authors.forename: Angela
authors.initials: A
authors.lastname: Lopedota
authors.forename: Adriana
authors.initials: A
authors.lastname: Trapani
authors.forename: Valentino
authors.initials: V
authors.lastname: Laquintana
authors.forename: Andrea
authors.initials: A
authors.lastname: Latrofa
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Trapani
authors.forename: Gaetano
authors.initials: G
authors.lastname: Liso
mesh_terms: 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*
chemical_list: 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