Inhibition of the solid state transformation of carbamazepine in aqueous solution: impact of polymeric properties.

The effects of polymers on the anhydrate-to-hydrate transformation of carbamazepine (CBZ) was investigated. The three types of polymers studied were polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) and substituted celluloses which included hydroxypropyl methylcellulose (HPMC) and methylcellulose (MC). Anhydrous CBZ was added to dilute aqueous polymer solutions and Raman spectroscopy measurements were collected to monitor the kinetics of the solution-mediated transformation to CBZ dihydrate. Polymers exhibiting the greatest inhibition were able to reduce the growth phase of the solution-mediated transformation and change the habit of the hydrate crystal indicating polymer adsorption to the hydrate crystal surface as the mechanism of inhibition. The results of the various polymers showed that short chain substituted celluloses (HPMC and MC) inhibited the CBZ transformation to a much greater extent than longer chains. The same trend was observed for PVP and PVA, but to a lesser extent. These chain length effects were attributed to changes in polymer confirmation when adsorbed on the crystal surface. Additionally, decreasing the percentage of hydroxyl groups on the PVA polymer backbone reduced the ability of the polymer to inhibit the transformation and changing the degree of substitutions of methyl and hydroxypropyl groups on the cellulosic polymer backbone had no effect on the transformation.

Influence of polymeric excipient properties on crystal hydrate formation kinetics of caffeine in aqueous slurries.

The influence of polymeric excipients on the hydrate transformation of caffeine (CAF) was studied. Anhydrous CAF was added to aqueous solutions containing different additives and the transformation to the hydrate form was monitored using in-line Raman spectroscopy. Various properties of two known inhibitors of CAF hydrate formation, polyacrylic acid (PAA) and polyvinyl alcohol (PVA), were investigated. For inhibition by PAA, a pH dependence was observed: at low pH, the inhibition was greatest, whereas no inhibitory effects were observed at pH above 6.5. For PVA, grades with high percent hydrolysis were the most effective at inhibiting the transformation. In addition, PVA with higher molecular weight showed slightly more inhibition than the shorter chain PVA polymers. A variety of other hydroxyl containing compounds were examined but none inhibited the CAF anhydrate-to-hydrate transformation. The observed inhibitory effects of PAA and PVA are attributed to the large number of closely spaced hydrogen bond donating groups of the polymer molecule, which can interact with the CAF hydrate crystal.

Manipulating hydrate formation during high shear wet granulation using polymeric excipients.

Active pharmaceutical ingredients (API) can undergo an anhydrate to hydrate transformation during wet granulation and this transformation may either result in mixed crystalline forms or an unwanted form in the final drug product. Previous studies have shown that it may be possible to inhibit this transformation with polymeric excipients. In this study, three model compounds, caffeine (CAF), carbamazepine (CBZ), and sulfaguanidine (SGN), were subjected to high shear wet granulation and phase transformations were monitored using in-line Raman spectroscopy. Wet granulation was performed in the presence and absence of various polymeric excipients to determine the extent of the inhibitory effects. Although several polymers had some retardation effect, cross-linked poly(acrylic) acid was found to completely inhibit the CAF transformation and both hydroxypropyl methylcellulose and cross-linked poly(acrylic) acid completely inhibited the CBZ transformation. For SGN, transformation to the hydrate was rapid, even in the presence of the polymers. The observed inhibitory effects were attributed to either specific interactions between the polymer and the API crystal or substantial water absorption by the polymer. There was also evidence from physical property testing that the inclusion of a small amount of inhibitory polymer did not significantly change the compaction or flow behavior of the final granulation.

Surface-enhanced Raman spectral measurements of 5-fluorouracil in saliva.

The ability of surface-enhanced Raman spectroscopy (SERS) to measure 5-fluorouracil (5-FU) in saliva is presented. The approach is based on the capacity of Raman spectroscopy to provide a unique spectral signature for virtually every chemical, and the ability of SERS to provide microg/mL sensitivity. A simple sampling method, that employed 1-mm glass capillaries filled with silver-doped sol-gels, was developed to isolate 5-FU from potential interfering chemical components of saliva and simultaneously provide SERSactivity. The method involved treating a 1 mL saliva sample with 1 mL of acetic acid, drawing 10 microL of sample into a SERS-active capillary by syringe, and then measuring the SER spectrum. Quality SER spectra were obtained for samples containing as little as 2 microg of 5-FU in 1 mL saliva. The entire process, the acid pretreatment, extraction and spectral measurement, took less than 5 minutes. The SERS of 5-fluorouridine and 5-fluoro-2'-deoxyuridine, two major metabolites of 5-FU, were also measured and shown to have unique spectral peaks. These measurements suggest that disposable SERS-active capillaries could be used to measure 5-FU and metabolite concentrations in chemotherapy patient saliva, thereby providing metabolic data that would allow regulating dosage. Tentative vibrational mode assignments for 5-FU and its metabolites are also given.

Influence of polymeric excipients on crystal hydrate formation kinetics in aqueous slurries.

Crystalline anhydrous active pharmaceutical ingredients (APIs) can potentially transform to the hydrate form during manufacturing processes involving water. The ability to understand and manipulate these transformations is important to maintain control of the solid state form of the API. The influence of various polymeric excipients on the anhydrate to hydrate transformation of caffeine, carbamazepine, and sulfaguanidine was investigated in this study. The transformation of the APIs in aqueous slurries was monitored using in-line Raman measurements and the resultant kinetic profiles provided insight into the inhibitory ability of the polymers investigated. The results showed that cross-linked poly(acrylic acid) inhibited the caffeine transformation and hydroxypropyl methylcellulose inhibited the carbamazepine transformation. None of the polymers tested were able to inhibit the sulfaguanidine transformation although some polymers were able to reduce the rate of the transformation with poly(vinylpyrrolidone) showing the greatest effect. It was found that the inhibitory polymers were able to either reduce crystal growth rates and/or increase the induction time preceding the nucleation event.

Hyphenation of Raman spectroscopy with gravimetric analysis to interrogate water-solid interactions in pharmaceutical systems.

A moisture sorption gravimetric analyzer has been combined with a Raman spectrometer to better understand the various modes of water-solid interactions relevant to pharmaceutical systems. A commercial automated moisture sorption balance was modified to allow non-contact monitoring of the sample properties by interfacing a Raman probe with the sample holder. This hybrid instrument allows for gravimetric and spectroscopic changes to be monitored simultaneously. The utility of this instrument was demonstrated by investigating different types of water-solid interactions including stoichiometric and non-stoichiometric hydrate formation, deliquescence, amorphous-crystalline transformation, and capillary condensation. In each of the model systems, sulfaguanidine, cromolyn sodium, ranitidine HCl, amorphous sucrose and silica gel, spectroscopic changes were observed during the time course of the moisture sorption profile. Analysis of spectroscopic data provided information about the origin of the observed changes in moisture content as a function of relative humidity. Furthermore, multivariate data analysis techniques were employed as a means of processing the spectroscopic data. Principle components analysis was found to be useful to aid in data processing, handling and interpretation of the spectral changes that occurred during the time course of the moisture sorption profile.

Surface-enhanced Raman spectra of VX and its hydrolysis products.

Detection of chemical agents as poisons in water supplies not only requires microg/L sensitivity, but also requires the ability to distinguish their hydrolysis products. We have been investigating the ability of surface-enhanced Raman spectroscopy (SERS) to detect chemical agents at these concentrations. Here we expand these studies and present the SERS spectra of the nerve agent VX (ethyl S-2-diisopropylamino ethyl methylphosphonothioate) and its hydrolysis products, ethyl S-2-diisopropylamino methylphosphonothioate, 2(diisopropylamino) ethanethiol, ethyl methylphosphonic acid, and methylphosphonic acid. Vibrational mode assignments for the observed SERS peaks are also provided. Overall, each of these chemicals produces a series of peaks between 450 and 900 cm(-1) that are sufficiently unique to allow identification. SERS measurements were performed in silver-doped sol-gel-filled capillaries that are being developed as part of an extractive point sensor.