The manufacture of fixed dose combination products using advanced pharmaceutical techniques for the treatment of cardiovascular disease and type II diabetes

Thesis by Jeremiah Kelleher, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, The University of Dublin

The thesis has focused on the use of continuous manufacturing techniques to produce fixed dose combination (FDC) products for the treatment of type II diabetes mellitus and cardiovascular diseases (CVDs). FDC products with monophasic and biphasic release profiles of the active pharmaceutical ingredients (APIs) were successfully manufactured via spray drying (SD), hot melt extrusion (HME), melt granulation (MG) and spray coating (SC). The impact of manufacturing technique on the products was studied, as well as the role excipients and their molecular makeup have on the final product characteristics.

Monolithic FDC products of hydrochlorothiazide (HCTZ) and ramipril (RAM), with an immediate release (IR) profile, were manufactured via HME and SD and the resulting physicochemical characteristics were analysed and compared with one another. The same formulations were used for both HME and SD. One of the challenges associated with RAM is that it is a thermolabile API and starts to degrade upon melting at its relatively low melting point of around 115°C. The addition of appropriate plasticiser (PEG 3350) successfully overcame the degradation of RAM seen during HME with the IR polymers chosen for the study (Kollidon® VA 64 and Soluplus®).

No degradation of RAM was observed during the SD process due to the lower temperatures the formulations were subjected to because of the suitable solvents available to dissolve the formulation contents. While all SD formulations were fully amorphous post processing, HME formulations were partially crystalline. In general, amorphous materials display higher solubility and higher dissolution rates when compared to crystalline materials. When the corresponding SD and HME formulations were compressed in the Wood’s apparatus and dissolution rates for both APIs studied, it was found the partially crystalline HME formulations displayed higher dissolution rates than the corresponding amorphous SD formulations in the relevant formulations. No release of API was observed from formulations containing Soluplus® due to the extensive swelling of the polymer. Surface topography studies of the compressed Wood’s apparatus discs revealed HME formulations to have significantly rougher surfaces than SD discs.

It is hypothesized the differences in surface texture give rise to varying turbulence levels at the hydrodynamic boundary layer and as a result, the dissolution rates differ from what might be expected when predicting release profiles based on the solid state of the formulations. While both manufacturing techniques were successful in producing IR monolithic FDC products, the comparative study highlights the importance of choosing an appropriate manufacturing technique to produce the final desirable product characteristics as well as avoiding degradation of the API.

Monolithic FDC products of metformin hydrochloride (MET) and sitagliptin phosphate (SIT), with a desired IR profile, were manufactured via MG and SD. The influence manufacturing technique as well as hydroxypropyl cellulose (HPC) polymer composition were analysed and studied for their influence on the final product characteristics. The same formulations were used for both MG and SD. Due to the large dosage size of MET, the quantities of excipients used for processing had to be kept to a minimum. Two HPC polymers were chosen for the formulations which varied in molecular weight and degree of hydroxypropoxy substitution. These different polymer characteristics led to differences in caplet characteristics irrespective of manufacturing technique, highlighting the role polymer composition has in producing final products for patient consumption. While final products were manufactured via both techniques and using both polymers, only one product, produced by MG and compressed at 8000 N, passed all the common compendial tests for IR oral tablets. The work highlights that MG is a suitable technique for producing high dose combination products and it may be more suitable than SD for a number of reasons. Firstly, it is seen as more environmentally friendly due to no solvents being required. Secondly, granules produced by the MG process have better flowability characteristics than powders produced via SD. Thirdly, while both MG and SD can be considered continuous manufacturing techniques due to constant input resulting in a constant output, SD powders have to be collected in a collecting vessel and removed before further processing whereas MG products can directly feed into the next phase of processing. The work also highlights that sufficient compression has to be applied to powers/granules to produce final products suitable for delivery to patients.

A delayed release formulation of simvastatin (SIM) was successfully manufactured via HME followed by coating via a fluid bed dryer (FBD) of an IR formulation of HCTZ and RAM to create a unique FDC product for the treatment of cardiovascular diseases (CVDs). Manipulation of formulation components such as plasticiser concentration, drug loading, and polymer ratio impacted the release profile of SIM to get it to the delayed desired release profile avoiding potential areas in the gut that can lead to degradation of the API. Once the core SIM formulation was manufactured, the extrudate was cut into pellets and spheronised into spherical pellets for coating. Various polymers and solvents as well as different processing parameters were trialled until successful application of the desired amount of HCTZ and RAM was achieved. The work carried out highlights the possibility of using HME to manufacture core material that can then be spheronised and coated using a FBD. Due to the flexibility of the coating, different drug loadings of various concentrations can be easily achieved.

A sustained released formulation of the thermolabile API, gliclazide (GLZ), was successfully manufactured via HME that gave a similar release profile to the marketed products available that are produced via direct compression. By manipulating formulation components such as polymer ratio, plasticiser selection and pH modifiers, the desired release profile, while also ensuring thermal degradation of the API was kept to a minimum, was achieved. The work highlights while thermal degradation is a significant factor in API degradation of thermolabile products during the HME process, local undesirable pH levels can cause degradation of the API also. Once the desired core GLZ formulation was manufactured, the extrudate was cut into pellets and spheronised into spherical pellets for coating. Pharmacoat® 603 was chosen as the polymer to aid SIT coating of the core material due to its film forming characteristics. Various solvent compositions were trialled during the coating process. The quantity of core material to be coated was also varied, with larger amounts of core material providing a higher coating efficiency due to a higher surface area being available for coating. The work highlights the possibility of producing sustained release thermolabile APIs via HME. It also highlights the flexibility of producing unique FDC products by applying additional API via SC.

The work conducted and presented in this thesis highlights the many modern continuous methods of manufacturing that can be applicable for FDC product production. Solvent free methods such as MG and HME may be more favourable due to being seen as a “greener” technology that is better for the environment due to no harsh solvents being used. While thermolabile API manufacturing via MG and HME may be difficult, the work in this thesis has shown with the correct excipients and conditions chosen, product manufacture via these methods is possible. While solvent methods such as SD and SC may be seen as less favourable production techniques, they still have a vital role in developing formulations with desirable characteristics and release profiles.
Download the thesis here: The manufacture of fixed dose combination products using advanced pharmaceutical techniques for the treatment of cardiovascular disease and type II diabetes