Solid-State Nuclear Magnetic Resonance of Pharmaceutical Amorphous Solid Dispersion

Most of the Active Pharmaceutic Ingredients (APIs), synthesized as crystalline forms, are subjected to dissolution problems although they exhibit thermodynamic stability. This poor solubility in water is related to the intrinsic physical-chemical characteristics of the crystalline state. From the point of view of pharmaceutical industries, these solubility issues represent a challenge to overcome. A general approach to improve the dissolution rate of a crystalline compound is to convert it into its corresponding amorphous form in a drug/polymer formulation matrix. These kinds of formulations are known as amorphous solid dispersions (ASDs); and is a promising strategy to increase the bioavailability of poorly soluble drugs and stabilize the thermodynamic instability of the amorphous species. The role of solid state NMR (ssNMR) is crucial to understanding the structure and the dynamics of ASD. Firstly, in my PhD course, I attended a safety induction at the University of Liverpool and at the Bristol-Myers Squibb. In addition, I received training on the NMR spectrometer equipped with different kind of ssNMR probe; during this training, I learnt the fundamental pulse sequences based on the cross polarization (CP) technique. Moreover, I have had a period to learn about ASD by studying some important reviews and papers. At the present, using NMR and calorimetric techniques, I have studied the chemical structure and physical properties of a range of suitable polymers to make an ASD, and I have started to study the polymorphism in two different APIs. The studied polymers are based on the hydroxypropyl methylcellulose acetate succinate unit with different ratio of acetate/succinate group and different particles granulometry. Polymers were purchased from ShinEtsu and used as received. They were: HMPC-AS-HG-spray dried and non-spray dried HMPC-AS-MF, HMPC-AS-LG, AQOAT-AS-MG, AQOAT-AS-HG and AQOAT-AS-LG. The studied APIs are Paracetamol and Naproxen. The commercial available most stable polymorph for both the drugs were purchased from Sigma-Aldrich. For each polymer and for both the drugs, by using the saturation recovery pulse sequence I have obtained the proton spin lattice relaxation time, T1(1H). This is a rapid and helpful NMR experiment to obtain crucial information to achieve good 13C CP experiments. By using the 13C CP experiments, with different contact time, it was possible to do an accurate assignment of the spectra peaks for each polymers and each drugs. As reported in the literature, the study of physical properties like carbon spin-lattice relaxation time, T1(13C), and carbon spin-lattice relaxation in the rotating frame, T1p, for each discrete component of an ASD are useful to estimate the final resulting formulation stability. For this reason, I obtained both T1(13C), and T1p, with different spin-lock radio frequency for each polymer and each drug. Finally, for each polymer and for both the commercial available crystalline drug forms, using the DSC facilities at Bristol-Myers Squibb, I achieved the glass transition temperature, Tg, and the melting temperature, Tm, values. This measure are useful to predict the finals formulation's Tg, at different drug/polymers loading. Starting from the most stable drugs crystalline forms, I have also attended to prepare all the know polymorphs by different re-crystallization methodologies. For all the resulting materials 13C CP has been run to determinate and discriminate different polymorphs. This work is on-going. To improve my scientific background in NMR spectroscopy I have attended scientific conferences and seminars.