Solvent Free Technologies for Polymer based Crystal Engineering and Drug Delivery

Abstract

Current research focuses on the effect of different continuous solid state shear based processing for the production of pharmaceutical amorphous system and cocrystals for poorly water soluble APIs. The S3M technology is getting first time reported for its application in pharmaceutical field and it is considered as technology with good potential for development of pharmaceutical dosage forms. The main objectives of this study include the effect of two solid state shear processes on the product properties in case of solid dispersions and cocrystals. Hot melt extrusion technology has been widely explored for the production of pharmaceutical solid dispersions and cocrystals, it would be helpful to compare how the new invented S3M technology will differ from the existing solid state shear process. The S3M has been also explored for the advantages over HME process in terms of residence time, plasticiser free dispersions, effect of process on degradation of drugs during processing. For this purpose, the process and material modifications during operation of these two technologies was important aspects of this study. The pharmaceutical drugs chosen for the solid dispersion purpose were carbamazepine, ibuprofen, glibenclamide which are BCS class II drugs and paracetamol from BCS class III drug was selected as model drug for solid dispersion manufacturing with PVP.

VA64, HPMCP HP55, HPMCAS, Ethyl cellulose as polymers. In case of cocrystals selected drugs were carabamazepine, caffeine, paracetamol and ibuprofen with co-formers nicotinamide, saccharin, salicylic acid, glutaric acid, oxalic acid, maleic acid. The selections of co-formers were done on the basis of functional group complementarity between drug and co-former. All the details about the pairs for cocrystals and for solid dispersions are given in experimental section. Carbamazepine has been explored in depth for solid dispersions with different polymers and with different co-formers in case of cocrystals. The effect of process variables and amount of shear applied during processing was deciding factor in product output and quality. The end product in case of both the solid dispersions and cocrystals varied in their physicochemical, morphological and drug release properties HME process needed addition of plasticisers during preparation of solid dispersions whereas S3M was plasticiser free process which gave good insight on how this will affect the product performance during evaluation studies. The solid dispersions in case of HME were had smooth surfaces and which are non-porous in nature whereas in case of S3M the solid dispersions were highly porous in nature. The differences in the structural and morphological features of solid dispersions somehow did not affect the drug release of drug during in-vitro dissolution studies and both the solid dispersions did not show much difference in drug release. In case of cocrystals processing on S3M it was observed that the S3M process is dependent on the use of polymer as process aid. For this purpose PEO, PVP VA64 and HPMCP HP55 were selected as model polymer as process aid during processing of cocrystals, out of which PEO has been explored widely as processing aid due to its process suitability, low melting and ability to withstand high shear during processing. PVP VA64 was used only in case of carbamazepine cocrystals with salicylic acid and HPMCP HP55 in case of caffeine cocrystals with maleic acid. The effect of concentration of PEO in case of carbamazepine cocrystals as processing aid was studied (concentration range 5%, 10%, 15%, 25% w/w). The concentration of PEO in case of HME cocrystals had direct effect on the drug release of drug dissolution studies which was reduced in case of higher concentration of PEO (25% w/w), which was not observed in case of S3M processes carbamazepine cocrystals. The product in case of cocrystals by S3M was thread like structures whereas in case of HME cocrystals were in form of screw shaped compact mass. The difference in morphological and structural properties of cocrystals did not had major effect on drug release in case of S3M process but in case of HME processed cocrystals the higher amount of polymer slowed the drug release.

The degradation studies in case of drugs carbamazepine, paracetamol were carried out whereas in case of polymer for HPMCP HP55 were carried out. It was found that HME processed samples showed higher degradation as compared to S3M processed one in both the cases solid dispersions and cocrystals. This can be attributed to high residence time in case of HME as compared to S3M process. The effect of two high shear processes HME and S3M had significant effect on the morphological and structural properties of the solid dispersions and cocrystals. The variation in the structural and morphological properties did not have direct effect on the drug release of drug during dissolution studies. HME and S3M both the processes had some positive and some negative aspects within them for processing of pharmaceutical dispersions and cocrystals.

In case of HME the use of plasticiser is mandatory to maintain low torque levels during processing and to avoid blockage of extruder barrel, whereas in case of S3M the process is plasticiser independent and processing of solid dispersion is very easy as compared to HME with low residence time. Processing of plain drug or co-former was easy in case of HME whereas in case of S3M processing it was mandatory to use polymer as processing aid specially during processing of cocrystals.

In case of process controls HME has excellent control over the process parameters which can be controlled and manipulated as per requirement, whereas S3M technology needs to have technical modifications to have better control over its processing parameters. The S3M can be a revolutionary technology for pharmaceutical industry once it is upgraded with better control and optimised process parameters.