Monitoring of multiple solvent induced form changes during high shear wet granulation and drying processes using online Raman spectroscopy.

Form changes during drug product processing can be a risk to the final product quality in terms of chemical stability and bioavailability. In this study, online Raman spectroscopy was used to monitor the form changes in real time during high shear wet granulation of Compound A, a highly soluble drug present at a high drug load in an extended release formulation. The effect of water content, temperature, wet massing time and drying technique on the degree of drug transformation were examined. A designed set of calibration standards were employed to develop quantitative partial least square regression models to predict the concentration of each drug form during both wet granulation and the drying process. Throughout all our experiments we observed complex changes of the drug form during granulation, manifest as conversions between the initial non-solvated form of Compound A, the hemi-hydrate form and the "apparent" amorphous form (dissolved drug). The online Raman data demonstrate that the non-solvated form converts to an "apparent" amorphous form (dissolved drug) due to drug dissolution with no appearance of the hemi-hydrate form during water addition stage. The extent of conversion of the non-solvated form was governed by the amount of water added and the rate of conversion was accelerated at higher temperatures. Interestingly, in the wet massing zone, the formation of the hemi-hydrate form was observed at a rate equivalent to the rate of depletion of the non-solvated form with no change in the level of the "apparent amorphous" form generated. The level of hemi-hydrate increased with an increase in wet massing time. The drying process had a significant effect on the proportion of each form. During tray drying, changes in drug form continued for hours. In contrast fluid bed drying appeared to lock the final proportions of drug form product attained during granulation, with comparatively small changes observed during drying. In conclusion, it was possible to simultaneously monitor the three forms in real time during wet granulation and drying using online Raman spectroscopy. The results regarding the effect of process parameters on the degree of transformation are critical for designing a robust process that ensures a consistent form in the final drug product.

Determination of process variables affecting drug particle attrition withinmulti-component blends during powder feed transmission.

The aim of this study was to determine the location of attrition of formulated API particles within a powder feed system using a Morphologi G3-ID system, an image analyzer with integrated Raman capability enabling classification of particles with respect to their chemistry, to extract the API size distribution from the blended sample. The study also aimed to investigate the impact of other process variables, such as feed screw speed, on the extent of attrition observed. The study demonstrated that attrition occurs in two zones of the powder feed system, at the bottom of the hopper at the interface with the feed screw, and also within the feed screw itself. In the situation of the attrition at the bottom of the hopper variations in the hopper fill level were not observed to change the extent of attrition observed. Variation of the feed screw speed was observed to affect the extent of API attrition, with the particle size within the formulation observed to decrease with increasing speed. The findings highlight that an understanding of the impact of unit processes, and variations in the associated processing conditions, is vital in order to fully understand the behavior and performance of pharmaceutical dosage forms.

Formulation and process design for a solid dosage form containing a spray-dried amorphous dispersion of ibipinabant.

Amorphous forms of poorly soluble drugs are more frequently being incorporated into solid dispersions for administration and extensive research has led to a reasonable understanding of how these dispersions, although still kinetically unstable, improve stability relative to the pure amorphous form. There remains however a paucity of literature describing the effects on such solid dispersions of subsequent processing into solid dosage forms such as tablets. This paper addresses this area by looking at the effects of the addition of common excipients and different manufacturing routes on the stability of a spray-dried dispersion (SDD) of the cannabinoid CB-1 antagonist, ibipinabant. A marked difference in physical stability of tablets was seen with the different fillers with microcrystalline cellulose (MCC) giving the best stability profile. It was found that minimising the number of compression steps led to improved formulation stability with a direct compression process giving the best results. Increased levels of crystallinity were seen in coated tablets most likely due to the exposure of the amorphous matrix to moisture and heat during the coating process. DSIMS analysis of the SDD particles indicated increased levels of polymer on the surface.

Development of oral extended release formulations of 6-hydroxybuspirone.

Reducing the maximum plasma concentration whilst maintaining the exposure was shown to ameliorate adverse events following the oral administration of 6-hydroxybuspirone. This observation, along with a desire to provide for once daily dosing of this compound, provided the basis for the development of an extended release formulation. Hydrophilic matrix tablets based on hydroxypropyl methylcellulose and containing citric acid to provide for an acid microenvironment were prepared and evaluated by in vitro drug release studies and in vivo pharmacokinetic and scintigraphic studies using samarium oxide (¹5³Sm) labelled dosage forms. The dosage forms were found to release the contained drug by a predominantly diffusion mechanism and the release rate was relatively independent of environmental pH. Following administration of the extended release formulations to volunteers, comparative pharmacokinetic data indicated that the extended release formulations provided for a reduction in the maximum plasma concentration of 64-70% relative to that provided by the same dose given as an oral solution, whilst maintaining exposure relative to the oral solution. By examination of absorption curves derived by Wagner-Nelson analysis of pharmacokinetic data it was noted that drug release in vivo correlated well with drug release observed in vitro and no marked change in rate of absorption was noted when dosage forms were located in and releasing drug in the colon. The robust control of drug release seen in vitro translated to a good in vivo performance.

Roller compaction: application of an in-gap ribbon porosity calculation for the optimization of downstream granule flow and compactability characteristics.

This paper reports the use of an in-gap ribbon porosity calculation for the optimisation of roller compaction ribbon parameters in order to control downstream granule and tablet properties for a typical pharmaceutical formulation. The study demonstrates the effect of changes to roll speed and roll gap on the relative level of ribbon compaction for ribbons with equivalent in-gap porosities. It is demonstrated that in-gap ribbon porosity can be applied to enable optimization of the downstream granule processability characteristics for a typical pharmaceutical formulation and an understanding of the control space of a roller compaction process.

Roller compaction: Application of an in-gap ribbon porosity calculation for the optimization of downstream granule flow and compactability characteristics.

This paper reports the use of an in-gap ribbon porosity calculation for the optimisation of roller compaction ribbon parameters in order to control downstream granule and tablet properties for a typical pharmaceutical formulation. The study demonstrates the effect of changes to roll speed and roll gap on the relative level of ribbon compaction for ribbons with equivalent in-gap porosities. It is demonstrated that in-gap ribbon porosity can be applied to enable optimization of the downstream granule processability characteristics for a typical pharmaceutical formulation and an understanding of the control space of a roller compaction process.

Amorphous drug-PVP dispersions: application of theoretical, thermal and spectroscopic analytical techniques to the study of a molecule with intermolecular bonds in both the crystalline and pure amorphous state.

We report the case of BMS-488043-PVP solid dispersions which when analysed using modulated DSC showed compliance with the Gordon-Taylor model, confirming ideal mixing behaviour of the two components. The nature or presence of stabilising interactions between drug and PVP could not be confirmed using this technique. Use of FT-IR, Raman and solid-state NMR spectroscopy confirmed the presence of stabilising hydrogen bond interactions between the drug and PVP. Similar interactions are present as intermolecular bonds in the crystalline and pure amorphous drug system. The Gordon-Taylor equation, as it is not predictive of the presence of intermolecular bonds such as hydrogen bonding in an amorphous dispersion, may underestimate the likely physical stability of solid dispersions which are produced and stabilised by these interactions.

Monitoring and end-point prediction of a small scale wet granulation process using acoustic emission.

A study to establish if acoustic emission could be used to monitor a small scale (120 g batch size) high shear granulation process and predict the process end-point, is reported. The robustness of the prediction model was further assessed by changing process variables. It is demonstrated that the technique is capable of repeatedly producing granules with consistent physical characteristics, such as particle size distribution and bulk density, despite changes in batch size and liquid dose rates. It is demonstrated that the model was affected by changes in impeller speed such that it was unable to identify a process end-point.