A Test of Character: How to improve drug-polymer miscibility
Duncan Stacey, sales & marketing director at Linkam Scientific, and Sheng Qi, reader in pharmaceutics at the School of Pharmacy, University of East Anglia discuss how to improve drug-polymer miscibility analysis using a new microscopy-based method.
A new microscopy-based method – thermal analysis by structure characterisation (TASC) – saves time, improves sensitivity and significantly reduces the amount of material required for drug-polymer miscibility analysis. TASC looks set to become a standard screening test in early drug development.
The problem of solubility
New chemical entities emerging from high-throughput screening programmes often exhibit unfavourable solubility properties, with some estimates suggesting that ‘approximately 60–70% of drug molecules are insufficiently soluble in aqueous media’1.
Issues with poor solubility can also be seen with pipeline candidates once they progress through the formulation and the drug development pathway towards the clinic.
As a result, the problem of solubility has been extensively studied, and formulators and drug development scientists are focused on finding novel ways to counter this undesirable characteristic. It is also no surprise that regulators have published a series of helpful definitions – for example, both the US and British Pharmacopoeias (USP and BP) define the solubility of drugs in seven categories, ranging from ‘very soluble’ to ‘practically insoluble’. In addition, according to the Biopharmaceutics Classification System (BCS), drugs fall into one of four categories (I – IV) based on their solubility and intestinal permeability properties.
Drug – polymer formulations
Polymers are widely used in pharmaceutical solid dosage forms as functional excipients to create matrices in which the drug can be dispersed. Such ‘so-called’ amorphous solid dispersions (ASDs) have been shown to significantly improve the absorption of some poorly soluble drugs in comparison to the crystalline form of the drug2.
The role of the polymer is to stabilise the amorphous form of the drug by reducing its molecular mobility and hence preventing it from crystallisation. In recent decades, ASDs have become a common formulation strategy to increase the bioavailability of poorly water-soluble compounds.
To successfully formulate such products for drug solubility enhancement, the drug needs to be highly miscible with the polymer3. However, the pre-formulation stage of screening suitable polymers is often a lengthy process, requiring the use of a range of semi-empirical, theoretical and experimental methods.
Drug–polymer miscibility is a critical parameter that has been shown to affect, for example, physical stability during storage, and dissolution rate of the final formulated product. The prediction of drug–polymer miscibility using theoretical considerations has been widely reported in the literature, and many experimental screening methodologies have been developed to assess individual drugs.
Nevertheless, there remains a significant need for additional rapid and sensitive analytical approaches that can be applied early in the drug development process – where the amount of drug material is often severely limited.
Now, a new, simple hot stage microscopy-based method – thermal analysis by structure characterisation (TASC) – has been successfully used to screen the miscibility of drug-polymer combinations.
A new analytical approach
TASC is a recently developed thermal imaging tool that can be used to study behaviour such as melting and thermal dissolution. As applied in the study described in this article, it is used to investigate changes in the features of crystalline drug particles as they are heated on a microscope slide in a linear fashion and melted on a thin layer of the polymer of interest.
Dr Sheng Qi and her group at the University of East Anglia (UEA) have a strong interest in ASD development and were seeking a new method for estimating drug-polymer miscibility. They have used TASC to develop this new application working closely with Linkam and professor Mike Reading.
For all the experimental work, a Linkam MDSG600 motorised heating/freezing stage, was used, connected to a Linkam imaging station equipped with reflective LED light source and a 10x magnification lens.
The stage is motorised in X and Y directions by precision micro-stepped motors that give micron repeatable position resolution and position recall. This enables a sample to be mapped, and positions of interest located so that temperature-controlled experiments can be carried out at those points. The accuracy and control of temperature (from < -195°C to 600°C) means that users can characterise fluid inclusions to better than 0.1°C and hold a stability of 0.001°C.
The new TASC method was compared to what is currently the most widely used method – differential scanning calorimetry (DSC). DSC measures the melting point depression of a crystalline drug due to the presence of a polymer, reducing the chemical potential of the drug at melting. This reduction in chemical potential is an indicator of drug-polymer miscibility.
Although the method has proven to be reliable, it has several drawbacks for routine screening. First, it is extremely time consuming and the accuracy of the estimation of miscibility is extremely dependent on the heating rates.
The detailed working principle of the TASC screening method is summarised in figure 1. A complete description of the experimental protocol and a full discussion of the results can be found in a recent publication4,5.
To verify the relevance and comparability of the new method, a large number of TASC data sets of the measurements of the crystalline drug particles melting on top of thin films of a wide range of typically used polymers in solid dispersion formulations was generated.
The full TASC plots of all drug-polymer pairs were analysed using principal component analysis (PCA) instead of comparing the depressed onset of melting as a single point measurement.
The PCA results confirmed the ability of TASC to sort the drug-polymer combinations based on the degree of the melting depression, which is directly related to the miscibility of the drug in the polymer and validates TASC as a useful and practical screening method of drug-polymer miscibility.
Conclusion
A new, rapid drug-polymer miscibility screening method based on TASC can give scientists the ability to quickly eliminate unsuitable candidate excipients. TASC is 20-40 times faster than conventional DSC methodology for detecting melting point depression. Important for early formulation and development stages, the new method provides actionable data from significantly less drug – only 1/1000th of the amount of material is needed to make the analysis. Compared to the current DSC methodology, the new TASC analysis also showed an increase in sensitivity.
References:
1. Gupta et al., Formulation Strategies to Improve the Bioavailability of Poorly Absorbed Drugs with Special Emphasis on Self-Emulsifying Systems. ISRN Pharmaceutics: 2013; 2013
2. Jermain SV, Brough C, Williams RO. Amorphous solid dispersions and nanocrystal technologies for poorly water-soluble drug delivery – An update. International Journal of Pharmaceutics. 2018;535(1):379-92.
3. Frank DS, Matzger AJ. Probing the Interplay between Amorphous Solid Dispersion Stability and Polymer Functionality. Molecular pharmaceutics. 2018;15(7):2714-20.
4. Alhijjaj M, Belton P, Fábián L, Wellner N, Reading M, Qi S. Novel Thermal Imaging Method for Rapid Screening of Drug-Polymer Miscibility for Solid Dispersion Based Formulation Development. Molecular pharmaceutics. 2018;15(12):5625-36.
5. Thermal Analysis by Structural Characterization (TASC) as a novel method for assessing heterogeneity in complex solid pharmaceutical dosage forms
6. Alhijjaj, M., Reading, M., Belton, P. & Qi, S., 3 Nov 2015, In : Analytical Chemistry. 87, 21, p. 10848–10855