Microscopic Imaging for Screening Solid Dispersions

To enhance the dissolution rate of poorly water-soluble drugs, solid dispersions have been widely employed as a formulation strategy. Yet, the selection of polymers to provide an effective and stable product is often challenging and time-consuming.

Drug-Polymer Miscibility

Drug-polymer miscibility is a key element in the development of polymeric based solid dispersions and impacts on the key properties of the final product and the processing methods that can be employed. These include loading efficiency, physical stability, and dissolution kinetics at the site of absorption [1].

Current methods for gauging drug-polymer miscibility are based on theoretical calculations which are complex, time-consuming, and inaccurate. These methods include melting point depression and solubility parameters [2].

Thermal Analysis Tool

Thermal microscopy in combination with Thermal analysis by structural characterization (TASC) is a recently developed novel thermal analysis tool that can be used for many pharmaceutical applications such as thermal dissolution analysis, glass transition kinetics, analysis of melting behavior and heterogeneity detection [3,4].

Together with the funding support of INTERREG, TASC has been developed further into an inexpensive and fast pre-formulation screening technique that needs just a few milligrams of a drug and excipients to permit formulators to screen solubility aiding selection and drug-polymer miscibility of the polymeric carrier and appropriate drug loading. This method can fast track the development of effective and stable solid dispersion based products.

Felodipine and its miscibility with a variety of pharmaceutical polymers have been well documented in literature [5, 6] and has been utilized in this work as a model drug and screened against ten of the most typically employed pharmaceutical grade polymers using TASC. In each of the polymers TASC was able to identify thermal drug dissolution and melting point depression.

Melting Point Depression

The melting point depression can be used to rank the drug-polymer miscibility and allow the selection of appropriate polymeric excipients and the drug dissolution process allows the more detailed probing of the solubility boundary of the drug in the polymer which can be used to help formulate solid dispersion products with good long-term stability.

As seen in Figure 1, TASC is able to detect the melting of crystalline felodipine by tracking the optical changes of the drug particle.

TASC signal of the melting of crystalline felodipine. The physical feature changes in the images at each frame during the heating programme was used to generate the TASC signal. The onset of melting of crystalline felodipine measured by DSC is 143 °C.

Figure 1. TASC signal of the melting of crystalline felodipine. The physical feature changes in the images at each frame during the heating programme was used to generate the TASC signal. The onset of melting of crystalline felodipine measured by DSC is 143 °C.

As shown in Figure 2, when the drug particles were placed on polymeric excipient films for screening the TASC outputs distinguish clearly between immiscible polymer excipients (no melting point depression) and miscible polymeric excipients (with highest level of the melting point depression).

The order of extent of melting depression of felodipine as a result of the different polymers was: Eudragit EPO > Soluplus > HPC > PVPVA> HPMC AS > PVP. With the other polymers, minimal or no depression in felodipine melting was seen. This ranking corresponds with existing literature data on the felodipine miscibility with these polymers [5, 7].

The TASC based melting point depression methodology and decision making associated with it on polymeric excipient selection is 20-40 times quicker than the conventional DSC technique.

TASC thermograms showing the melting point depression of felodipine from I crystals caused by the presence of Eudragit E PO using 20 °C/min heating programme (n=5).

Figure 2. TASC thermograms showing the melting point depression of felodipine from I crystals caused by the presence of Eudragit E PO using 20 °C/min heating programme (n=5).

After a suitable polymeric candidate is chosen, the accurate detection of the solubility boundary of the drug in the polymer is critical for creating long-term stable solid dispersions. TASC can be employed to probe the maximum drug concentration which can be loaded in compatible polymers. When the maximum drug solubility in the polymer is reached, the thermal dissolution behavior shows saturation, as seen in Figure 3.

For example, utilizing Soluplus as suitable polymeric candidate for producing felodipine solid dispersions, the saturation limit of felodipine in Soluplus is around 30-40% w/w. The long-term stability data produced was consistent with the solubility measured by TASC technique.

Probing the thermal dissolution of felodipine form I particles above 0-100% w/w felodipine-soluplus solid dispersions using 20 °C/min.

Figure 3. Probing the thermal dissolution of felodipine form I particles above 0-100% w/w felodipine-soluplus solid dispersions using 20 °C/min.

Conclusion

The potential of utilizing TASC to detect and distinguish the different degrees of miscibility of drug-polymer combination gas has been clearly demonstrated by the results of this study. Its suitability as an effective technique for estimating the solid solubility of drug in polymer has also been shown. This feature can be employed as an inexpensive and rapid screening technique during the preformulation stage of solid dispersion based products.

Muqdad Alhijjaj1, Peter Belton2, Laszlo Fabian1, Mike Reading3, Sheng Qi1*

1School of Pharmacy, University of East Anglia, Norwich, Norfolk, UK, NR4 7TJ;

2School of Chemistry, University of East Anglia, Norwich, Norfolk, UK, NR4 7TJ;

3Cyversa, Norwich, Norfolk, UK

Acknowledgements

The authors thank INTERREG EU and Linkam Scientiöc for supporting this study. Many thanks for Ashland, BASF and Evonik for supplying the polymers.

References

  1. Liu, J., Y. Xiao, and C. Allen, 2004. Journal of Pharmaceutical Sciences 93(1), 132-143.
  2. Tian, Y., Caron, V., Jones, D.S., Healy, A.-M., Andrews, G.P., 2014. Journal of Pharmacy and Pharmacology 66, 256-274.
  3. Alhijjaj, M., Reading, M., Belton, P., Qi, S., 2015. Analytical Chemistry 87, 10848-10855.
  4. Reading, M., Morton, M., Antonijevic, M., Grandy, D., Hourston, D., Lacey, A. 2014 Microscopy: advances in scientific research and education; Formatex: Badajoz, Spain Vol. 2, 1083– 1089.
  5. Yiwei, T., Jonathan, B., Elizabeth, M., David, S. J., Shu, Li., Gavin, P. A., 2013. Molecular Pharmaceutics 10 (1), 236-248
  6. Alhijjaj, M., Yassin, S., Reading, M., Zeitler, J.A., Belton, P., Qi, S. 2017. Pharmaceutical Research 34(5), 971-89.
  7. Alhijjaj, M., Belton, P., Qi, S., 2016 European Journal of Pharmaceutics and Biopharmaceutics 108:111-25.

This information has been sourced, reviewed and adapted from materials provided by Linkam Scientific.

For more information on this source, please visit Linkam Scientific.

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