Release adjustment of drug combinations with different drug solubility

Formulation issues of drug combination in one dosage form could be due to different solubility of drug which will give different release profile. The objective of present study is therefore to adjust the release of two drugs of different solubility in drug for controlled release drug delivery as matrix tablet and multilayer pellet system. As tablet system, employing direct compression method, irrespective to type of polymers, release of propranolol HCl was much faster than carbamazepine due to solubility differences. The modified method of simple mixing of EC with HPMC, followed by direct compression method, resulted in slower release of propranolol HCl. This retardation was attributed to increase in total polymer loading after the presence of EC. In order to provide an additional diffusion barrier, propranolol HCl powder was granulated to form drug granules with reduced drug release prior compression with carbamazepine and other excipients as matrix tablet. The increase in particle size of granules resulted in a decrease in both propranolol HCl and carbamazepine release. To provide more homogeneous coating of propranolol HCl particle, granulation process was performed in fluid bed granulator. This method of granulation resulted in better retardation of propranolol release either as granule or after compression into matrix tablets. Release adjustment from matrix tablet system can be conducted by controlling the erosion rate of the matrix which enables to provide faster release. Blending of HPMC matrices with lower molecular weight HPMC increased erosion rate hence faster drug release. Retardation of propranolol HCl performed by layering propranolol HCl onto non-pareils followed by coating with ethylcellulose prior to compression together with carbamazepine powder into HPMC tablets resulted in an almost similar release of propranolol HCl and carbamazepine (f2 factor = 68.29). The adjustment on permeability of the film coating (including coating level and HPC content as pore former of propranolol HCl pellets), changed the release profile of propranolol HCl without remarkable effect of the carbamazepine release. In contrast, by adjusting erosion rate using different HPMC blends as matrix and different particle size of carbamazepine, not only the release of carbamazepine which was affected but also propranolol HCl which associated with more pellets released from the matrix. The release profile of drugs with different solubility could not be adjusted by using conventional polymeric coating system (as drug blend with a single layer coating). Therefore, drug with high solubility (D1) was coated by less permeable coating (C1) consecutively layered with low soluble drug (D2) and coated with more permeable coating (C2). The permeability of first and second coating were adjusted with the HPC content and coating level. Applicability maps to improve flexibility in the formulation and to achieve variety of possible release (expressed as t80%) for drug 1 and drug 2 were prepared. Formulation to provide pellets with faster release of propranolol HCl, faster release of carbamazepine or both of drug are released in the same time had been developed from the applicability map for particular t80 values. The effect of HPC as porogen on drug release from EC coated single layer pellets and more complex systems (multilayer pellets) with regard to drug combination was also studied. Plotting the drug release (expressed as t80%) of the individual formulations vs. the corresponding HPC content of the film coatings revealed a sigmoidal pattern which reasonably well represented by a cumulative normal distribution. The distribution function of the model is valid for the entire profile in the release phase for the mean values are the same (22.5 % w/w). Plotted drug release vs. HPC content for different coating levels revealed the same sigmoidal relationship (identical mean and SD). Hence, drug release of different coating level using different HPC content can be predicted, connecting both relationships. The quantitative basis of the findings from single layer system can be applied to multilayer pellet system either for first drug (high solubility) or second drug layer (low solubility) indicating the feasibility to extend the mathematical model to more complex systems or to drugs of different physico-chemical properties.

Author dc:creator

• Chaerunisaa, Anis Yohana

• Release adjustment
• drug combination
• pellets
• matrix tablets

Licence dc:rights.uri

• http://www.fu-berlin.de/sites/refubium/rechtliches/Nutzungsbedingungen

Language dc:language

eng

Identifier URI

http://dx.doi.org/10.17169/refubium-9142

OAI record oai:identifier

https://refubium.fu-berlin.de/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Arefubium.fu-berlin.de%3Afub188%2F4943