Solid-State Nuclear Magnetic Resonance of Pharmaceutical Amorphous Solid Dispersion

Lead Research Organisation: University of Liverpool
Department Name: Chemistry


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.


10 25 50

Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/R51231X/1 01/10/2017 30/09/2021
1959812 Studentship EP/R51231X/1 01/10/2017 31/12/2021 Andrea Pugliese
Description EPSRC NPIF Innovation Placement Award - placement with Bristol-Myers Squibb
Amount £1,906 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 10/2019 
End 01/2020
Title Simple method to access acetyl (A) and succinyl (s) ratio in the Hydroxypropyl methylcellulose acetate succinate polymer (HPMC-AS) 
Description Our simple methods was reported in the literature in 2020. Using our methods, it is demonstrated that it is possible to estimate the various contents of A and S directly from the experimentally obtained 13C NMR spectra to capture the different grades of HPMC-AS. Generally the A/S ratio is achieved by the vendors using the rules reported in the US/Japan Pharmacopeia using different analytic techniques. 
Type Of Material Technology assay or reagent 
Year Produced 2020 
Provided To Others? Yes  
Impact The research method allowed a simple and quick access to A/S ratio. This NMR based method can be included to the already existing analytical methods in the industrial field. On the other hand, on the pharmaceutical point of view, by the possibility of to access at the A/S easily, using our method, it is possible to check the he A/S ratio in the sample to maximise the stabilisation effect of the polymer on the final solid dispersions. 
Description Bristol Myers Squibb, pharmaceutical company based in UK and US 
Organisation Bristol-Myers Squibb
Country United Kingdom 
Sector Private 
PI Contribution At the moment, the main contribution made by my research group is a published paper "Solid state nuclear magnetic resonance studies of hydroxypropylmethylcellulose acetyl succinate polymer, a useful carrier in pharmaceutical solid dispersions" on the Magnetic Resonance in Chemistry Journal. This work systematically assgined 13C in HPMC, HPMC-A, HPMCS, and HPMCAS-L/M/H in ssNMR spectra. In order to achieve the accurate assignment, authors started peak assignment with HPMC, followed by HPMC-A and HPMC-S, and then ended with HPMCAS. This work is important to establish the basic understanding of 13C peak assignment for pharmaceutic polymers, HPMC and HPMCAS. This study has the potential impact in pharmaceutics, considering the broad application of HPMC-based polymer in amorphous solid dispersion.
Collaborator Contribution The contribution made by the partners consist in a continues availability of resource, and instrumental availability both in the UK and the US facilities.
Impact 1) Solid state nuclear magnetic resonance studies of hydroxypropylmethylcellulose acetyl succinate polymer, a useful carrier in pharmaceutical solid dispersions paper published on the Magnetic Resonace in Chemistry
Start Year 2017