Vibrational spectroscopy to monitor controlled drug release from hydrophilic matrices
Authors:   , Zahoor Farah Deeba 
Published: May 2022

Approximately 40% of drugs currently marketed and 90% of all drugs under development show poor and varied aqueous solubility at the different pH values encountered along the gastrointestinal tract. The pH-dependent release profile exhibited by these drugs often leads to poor bioavailability and ultimately means that many do not make it to licence. To mitigate against this and to inform future drug development, it is important to understand the dissolution behaviour of these types of drugs at a molecular level. This thesis explores the use of ATR-FTIR imaging to gain an insight into the within-tablet dynamics of a sparingly soluble, weakly basic drug that has been incorporated into a hydrophilic matrix. This approach provides a chemical insight into the nature of drug, polymer matrix, excipients and water in a formulation undergoing dynamic changes including ionisation, dissolution, hydration, swelling and particle dislocation. Specifically, this work uses tablets manufactured using an HPMC polymer matrix incorporating 20% w/w itraconazole as the model drug which has a pKa of 3.7 and is practically insoluble at pH 7, both with and without the addition of the organic acid modifiers (citric acid, betaine HCl, cysteine HCl and glycine HCl) to control the local pH. In placebo HPMC tablets, ATR-FTIR imaging, supplemented by optical imaging, showed that hydration and swelling was independent of the pH of the media. However, when the ionic strength of the hydrating medium was adjusted, rapid formation of the gel layer was observed at low ionic strength, while increased ionic strength was shown to interfere with HPMC hydration, resulting in the suppression of the expansion of the gel layer. Hydration and dissolution studies conducted on HPMC tablets loaded with 20% w/w IT were limited to the use of low ionic strength media only. From the dissolution studies, the release of IT from these tablets was shown to be significantly greater at pH 1.5 when compared with that at pH 7. Optical measurements showed that the swelling of 20% w/w IT loaded HPMC tablets was greater at pH 1.5 over the period of the hydration in comparison to the pH 7 environment. ATR-FTIR imaging data revealed that at pH 1.5 the IT was ionised, becoming soluble and there was evidence of IT particle translocation into the diffusion front and eventually out into the surrounding medium. However, at pH 7, the IT remained in the free base form, largely within the tablet core and the swelling front, with less evidence of IT particle translocation. From both the optical measurements and ATR-FTIR imaging studies, it was shown that the swelling capacity of the gel layer in IT loaded tablets was reduced at pH 7 in comparison to pH 1.5 indicating that the poor solubility of IT retarded hydration. Exploring the impact of organic pH modifiers on the release of IT from the HPMC matrix at a 10% w/w and 30% w/w loading, enhanced dissolution at pH 7 of the IT was observed in comparison to tablets without any modifier. From both the optical imaging and ATRFTIR imaging data, the gel layer expansion was shown to be greater at higher pH modifier loading for all systems. However, the magnitude of swelling differed between the modifier systems over the hydration period and a greater amount of swelling was observed with the betaine HCl and citric acid in comparison to the cysteine HCl and glycine HCl. The results indicated that, of the organic acid modifiers selected, tablets containing cysteine HCl provided the greatest enhancement of release of IT. These findings were consistent with the ATR-FTIR imaging results, where the greatest reduction in the intensity of the spectral band assigned to the free base form of IT, was also observed in tablets containing the cysteine HCl modifier.