Effect of coating excipients on chemical stability of active coated tablets.

The objective of this study was to understand the impact of coating excipients on the chemical stability of active pan coated peliglitazar, which was prone to acid as well as base-catalyzed degradation. Four different coating formulations containing either polyvinyl alcohol (PVA) or hydroxypropyl methylcellulose (HPMC) as a coating polymer and triacetin (glycerol triacetate) or polyethylene glycol (PEG) as a plasticizer/detackifier were used for coating of peliglitazar in a perforated pan coater. Tablets of one-milligram strength were manufactured by suspending the drug in the coating suspension and spray coating onto inert core tablets. The active coated tablets were placed on stability (40 °C/75% RH) in high-density polyethylene (HDPE) bottles in closed condition with desiccants or in open condition. Tablet samples were withdrawn and analyzed for degradants using a stability-indicating HPLC method. The overall stability for the film-forming polymer-plasticizer/detackifier combination showed the rank order: HPMC-triacetin > PVA-triacetin > HPMC-PEG > PVA-PEG. Higher stability of triacetin systems over PEG systems was attributed to lower solubility of peliglitazar in triacetin coating systems. For the same plasticizer/detackifier, higher stability of HPMC over PVA-based formulations was attributed to lower solubility and mobility of peliglitazar in HPMC compared with the PVA-based coating.

Investigating gabapentin polymorphism using solid-state NMR spectroscopy.

Solid-state NMR spectroscopy (SSNMR), coupled with powder X-ray diffraction (PXRD), was used to identify the physical forms of gabapentin in samples prepared by recrystallization, spray drying, dehydration, and milling. Four different crystalline forms of gabapentin were observed: form I, a monohydrate, form II, the most stable at ambient conditions, form III, produced by either recrystallization or milling, and an isomorphous desolvate produced from desolvating the monohydrate. As-received gabapentin (form II) was ball-milled for 45 min in both the presence and absence of hydroxypropylcellulose (HPC). The samples were then stored for 2 days at 50°C under 0% relative humidity and analyzed by 13C SSNMR and PXRD. High-performance liquid chromatography was run on the samples to determine the amount of degradation product formed before and after storage. The 1HT1 values measured for the sample varied from 130 s for the as-received unstressed material without HPC to 11 s for the material that had been ball-milled in the presence of HPC. Samples with longer 1HT1 values were substantially more stable than samples that had shorter T1 values. Samples milled with HPC had detectable form III crystals as well. These results suggest that SSNMR can be used to predict gabapentin stability in formulated products.

Studies on the instability of chlorhexidine, part I: kinetics and mechanisms.

The objectives of the studies presented herein were to determine the pH-dependent chlorhexidine (CHD) degradation scheme, to determine the rate laws, and to propose reasonable mechanisms for CHD hydrolysis in aqueous solutions. A series of degradation kinetic studies was conducted at 90.0 °C using reaction mixtures containing 0.10 mM CHD prepared in the pH range of 0.5-9.0 using hydrochloric acid, sodium hydroxide, acetate, phosphate, or 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffers at a constant ionic strength of 0.500 M. Concentration-time profiles for all degradation products, intermediates, and substrates were determined by high-performance liquid chromatography (HPLC). Degradation products and intermediates were identified using a combination of liquid chromatography-mass spectrometry, kinetic analysis, and HPLC comparison with authentic compounds. pH-dependent degradation scheme and rate laws were parameterized using nonlinear regression. The direct formation of p-chloroaniline (PCA) from CHD is the major pathway in acidic conditions, whereas the indirect formation of PCA via the formation of p-chlorophenylurea is the main pathway in alkaline conditions.

Kinetic model for solid-state degradation of gabapentin.

Gabapentin degrades directly to gabapentin-lactam (gaba-L) in the solid state. The objective of this study was to formulate a drug degradation model that accounted for the environmental storage conditions and mechanical stress (prior to storage) on lactamization kinetics. The effects of mechanical stress on drug degradation kinetics were determined by milling gabapentin in a FRITSCH Planetary Micro Mill for 0 and 60 min. The resultant gabapentin powder was stored at 40 °C-60 °C and 5%-30% relative humidity. The rate of gaba-L formation was measured by high-performance liquid chromatography. An irreversible two-step autocatalytic reaction scheme was fit using nonlinear regression methods. The resultant kinetic model was used to predict the time-dependent concentration of degradant of gabapentin tablets prepared under various exemplary manufacturing conditions, thereby demonstrating the ability of the model to link manufacturing variation and chemical stability in solid-state gabapentin formulations.

The stabilizing effect of moisture on the solid-state degradation of gabapentin.

Gabapentin is known to undergo intramolecular cyclization to form a lactam (gaba-L) with concomitant loss of water. Gabapentin was milled in a planetary mill for 15-60 min. Unmilled and milled gabapentin were stored at 50°C with relative humidity ranged between 5% and 90%. The unmilled and milled samples were assayed for gabapentin and gaba-L by reversed phase-high-performance liquid chromatography and also subjected to powder X-ray diffraction, solid-state nuclear magnetic resonance and surface area analyses. The rates of lactamization in the milled gabapentin samples correlated to increased surface area, milling duration, and in-process lactam levels. This effect of milling could not be explained solely by the increase in surface area with increased milling time but was more likely due to increased regions of crystal disorder caused by the mechanical and thermal milling stresses. The lactamization rate of milled gabapentin samples was greatest in the presence of the lowest humidity conditions and dramatically decreased with increasing humidity. In particular, milled gabapentin appeared to be much more stable at humidity levels greater than 31% RH. This finding could not be attributed to the possibility of lactam hydrolysis at high humidity but rather to a competitive annealing process wherein milling-induced crystal defects were lost upon exposure to atmospheric moisture thereby stabilizing the milling-damaged drug substance.