Purpose: With the term “coamorphous” (COA) first coined in 2009, interest in this area has slowly been gaining traction as the benefits become further highlighted. In particular, it is well accepted that amorphous materials offer a higher apparent solubility and dissolution rate relative to the crystalline form of a drug (2). Despite this, the lack of long-range order, high internal energy and hence, thermodynamically instability, associated with an amorphous form means conversion to the crystalline form over time is probable. There are many strategies to stabilise the amorphous form, COA being one of the most recent and interesting approaches. Binary COA systems incorporate a small molecule as a stabiliser, as opposed to high MW polymers as with traditional amorphous solid dispersions. Interestingly, there are recent reports that detail higher drug loadings, reduced hygroscopicity [due to absence of hydrophilic polymeric carrier] and enhanced stability relative to amorphous solid dispersions In this work, a drug-excipient combination (hydrochlorothiazide-nicotinamide), which has previously been reported as a cocrystal, has been prepared as a COA system.
Methods: The amorphous form of HCT was prepared by heating above its melting point in a DSC before quench cooling and reheating. Recrystallisation was observed during the standard cooling step for NCT within the DSC (heating rate) and in that case liquid nitrogen was used in order to generate amorphous NCT. Physical mixtures of HCT and NCT were prepared by grinding in mortar and pestle prior to analysis. Aluminium DSC sample pans containing 3-6 mg of sample were prepared and heated as detailed below. Samples were analysed using DSC Q20 (TA instruments, Hertfordshire, U.K.), heated from 30 °C at 10 °C/min to a specified temperature between 130 °C and 180 °C, before quench cooling to -40 °C. Each sample was then reheated to above the melting point of HCT to observe the presence of COA material or any residual crystalline material. Mol fractions of drug:excipient were also varied in different ratios from 0.0-1.0 HCT, this was to assess the coamorphous-forming ability of the system in different environments. Raman spectroscopy (contact probe, Kaiser Optical Systems Inc., Ann Arbour, U.S.A.) was used to monitor the real time structural change upon heating and after quench cooling.
Results: Heating of the equimolar physical mixture beyond the melting point of NCT resulted in formation of the previously reported cocrystal of HCT-NCT, with subsequent melting at 174 °C (3). It was found that heating the mixture beyond the onset (165 °C) of the cocrystal melt, followed by quench cooling,allowed the formation of a COA system. Heating to temps below 165 °C did not result in COA formation. The COA system was characterised by a single glass transition (Tg), at approximately 40 °C, observed between the two Tg’s of the individual components. Formation of COA from molten cocrystal was further confirmed by a proportional increase in Tg ΔCp with increasing temperatures (170, 175 and 180 °C). Additionally, the Tg temperature of the COA increase as the maximum temperature during the first heat increased. At 165 oC, there is only a small proportion of cocrystal in the molten phase, which would indicate a lower proportion of COA will be formed on cooling. In this instance it is thought that the presence of remaining amorphous NCT depresses the Tg to a lower temperature. HCT/NCT COA was found to be most stable at 0.4 mol fraction HCT, showing the highest Tg temperature. Increasing HCT loading beyond this point had no significant effect. Raman spectroscopy was employed to provide real-time spectral information as the cocrystal was heated to various temperatures beyond the onset of melting. Significant spectral changes were observed (peak shifts, new peaks and varying peak intensity). Specific changes in regions 1040 and 3390 cm-1) of the Raman spectra were attributed to reduced hydrogen bonding of sulphonamide groups on hydrochlorothiazide and amide groups on NCT upon formation of the COA.
Conclusion: A new binary COA system has been identified, formed from quench cooling of the corresponding cocrystal melt. Optimisation of the molar ratio of the components has been carried out to obtain the most stable and favourable combination. Raman spectroscopy was successfully used to monitor the structural changes during cocrystal formation and subsequent transformation into the COA form.