Many pharmaceutical materials are developed in solid form for practical reasons, such as storage and transportation and ease of administration. However, for them to be effectively absorbed by the body, they must be soluble in an aqueous environment.
Polymorphism in pharmaceutical solids, or the ability of a substance to exist in more than one molecular arrangement, has significant implications on both the processing and the performance of solid pharmaceutical products. The resulting nature of such a material is its existence in more than one polymorphic form, which differ in their physiochemical properties, such as dissolution and solubility, chemical and physical stability, flowability, and melting point.1 Depending on the particular molecular arrangement, the polymorphic forms could vary in their relative stabilities; with the metastable forms eventually converting to the most stable form. The forms also differ in various important drug outcomes like efficacy, bioavailability and toxicity. Studying these phase transformations is important in understanding the properties and implications of these polymorphic forms.
During development, pharmaceuticals must be precisely characterized for information such as the temperature at which undesirable phase changes will occur, such as crystallization. The study of polymorphic forms and phase transformations enables suitable API/excipient form selection, which can influence shelf-life and drug potency. Regulatory agencies are in fact demanding this information.
Various techniques could be employed to characterize polymorphs, including thermal analysis (Differential Scanning Calorimetry (DSC) and thermogravimetric analysis (TGA)), Infrared (Fourier Transform Infrared FT-IR), spectroscopy, Raman spectroscopy, powder X-ray diffraction (XRD), single crystal XRD, solid state NMR, terahertz spectroscopy, optical and electron microscopy and incoherent inelastic neutron scattering (IINS).
Thermal properties of polymorphs are important to analyze and DSC is the most common and efficient technique, as it allows the evolution of these transformations to be followed as a function of temperature or time, while being highly sensitive to minute calorimetric fluctuations.2 It provides valuable information about the physical and energy properties of the substance, such as glass transitions, phase changes, melting points, crystallization and degradation temperatures, all to a high degree of temperature accuracy.
Nonetheless, sometimes it is difficult to build a clear picture of what is happening to the sample as it goes through a phase transition from just the heat flow signal provided by the DSC, and thus visualizing these processes adds valuable information. In addition, subtle transitions such as solid-solid transitions could be missed in the DSC if they happen over a wide temperature range.
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The Linkam DSC450 stage allows visualization of the sample during a DSC experiment. It enables the user to measure glass transitions and melting behavior of a wide range of substances, while accurately controlling temperature from -150 °C to 450 °C. The atmosphere of the stage can also be purged with inert gas as required by the user. The LINK Digital Imaging module enables additional information to be obtained by correlating optical changes such as color or morphology with temperature. Polymorphic changes can also occur due to water uptake in higher humidity atmospheres, the likes of which can be precisely replicated and modelled using Linkam’s Relative Humidity controller.
In a recent study,3 the Linkam DSC450 was used to observe phase transitions in flufenamic acid (FFA). A brief discussion of the study follows.
Method
The Linkam DSC450 stage was used in studying FFA, one of the most polymorphic pharmaceuticals with a record of nine known polymorphic forms.4 The aim was to study crystallization from the amorphous phase obtained by melt quenching. Form I was obtained by spray drying and was first heated in the DSC450 up to its melting point, after which it was allowed to cool down to room temperature before re-heating at a 10 °C/min heating rate to 160 °C. For the second part of the study, a polymer polyvinylpyrrolidone (PVP) was added and the sample analyzed following the same procedure, with the addition of structural analysis of the captured images.
Results
As shown in Figure 1, form I had an onset melting point of ca. 132 °C, while the re-heated sample melted at a lower temperature (onset of ca. 122 °C). No re-crystallization was observed in the second heating cycle, which indicated that upon cooling a metastable form recrystallized from the melt.
The effect of adding a polymer (PVP) is evident in Figure 2, where it appeared that the sample did not crystallize upon cooling, but rather formed an amorphous phase. Heating the amorphous phase caused the re-crystallization of FFA, followed by a solid-solid transition and then a melt. These events appear as two exothermic transitions, followed by a sharp endotherm.
The solid-solid transition is subtle in the DSC thermogram, but is very clear from the signal obtained from employing an image analysis technique (Thermal Analysis by Surface Characterization, TASC) shown in Figure 2c. The melting peak has an onset temperature of ca. 119 °C, which is lower than that of the form crystallized from the melt without the presence of the polymer. The TASC signal also shows that melting is detected visually before the DSC signal starts to change.
Conclusion
In this work, polymorphic transitions in the pharmaceutical material flufenamic acid were studied with the Linkam DSC450 stage, which combines optical microscopy with differential scanning calorimetry.
The power of the complementary technique was evident with the increased sensitivity for detecting subtle transitions such as solid-solid transition by analyzing the optical images.
The Role and Potential of TASC
TASC (Thermal Analysis by Structural Characterization), as mentioned in the above study, is a novel, new image analysis technique that can be used to analyze highly localized changes in sample features that occur during heating or cooling.5 For example, when a crystalline material progresses through glass transition to melting, there is significant loss of structure as the material changes from solid to molten form. The heat-flow curve produced by a DSC is an average of all the individual crystals that make up the material in the sample pan. Thus, DSC can be thought of as a “bulk” characterization method for all the material in the sample pan.
TASC has the unique ability to track and quantify optically local transition temperatures, allowing different points on a sample to be identified and TASC’s ability to measure many different locations across the sample makes it ideal for studying sample inhomogeneity. TASC and DSC can be seen as complementary techniques.
Optical DSC is clearly a powerful tool and, when combined with TASC, can provide unique insights into material properties. TASC can also be used in conjunction with standard thermal microscopy, as is shown in the following study.
Solid dispersions are widely used for improving the dissolution rate of poorly water-soluble drugs. The selection of the most appropriate polymer is often problematic and time consuming. Drugpolymer miscibility is a critical parameter in the development of polymeric based solid dispersions and is key to the properties of the final product.
Thermal microscopy in combination with TASC, is a tool that can be used for many pharmaceutical applications, including dissolution analysis, glass transition kinetics, analysis of melting behavior and heterogeneity studies.
TASC for Screening Solid Dispersions
TASC has been used as a rapid pre-formulation screening tool for solid dispersions. Drug excipient combinations can be screened for miscibility and solubility aiding the selection of polymeric carriers and appropriate drug loading. In a recent study, felodipine was used as a model drug and screened against ten commonly used pharmaceutical grade polymers using TASC.6
TASC was able to detect melting point depression and thermal drug dissolution in each of the polymers. The extent of the melting point depression was then used to rank the drug-polymer miscibility enabling the selection of the appropriate polymeric excipients. The drug dissolution process allowed more detailed probing of the solubility boundary of the drug in the polymer. This can be used for formulating solid dispersion products with good long-term stability.
Drug particles were placed on polymeric excipient films for screening. The TASC output was clearly able to distinguish between miscible polymeric excipients and immiscible excipients.
Once a suitable polymeric candidate is selected, accurate detection of the solubility boundary of the drug in the polymer is vitally important for producing long-term stable solid dispersions. TASC can be used to probe the maximum drug concentration that can be loaded in compatible polymers.
These studies show the potential of TASC, an image analysis technique combined withthermal microscopy and optical DSC, to detect and distinguish the different degrees of miscibility of drug-polymer combinations and its suitability as an effective tool for estimating the solid solubility of drug in polymer. This feature can be used as a rapid and inexpensive screening method during the pre-formulation stage of solid dispersion based products.
References
- Rodrıģuez-Spong, B., Price, C. P., Jayasankar, A., Matzger, A. J. and Rodrıģuez-Hornedo, N. R. 2004. General principles of pharmaceutical solid polymorphism: A supramolecular perspective. Advanced Drug Delivery Reviews 56(3): 241-274.
- Gaisford, S. and Saunders, M. 2012. Physical form i – crystalline materials. Essentials of pharmaceutical preformulation, John Wiley & Sons, Ltd: 127-155.
- Studying phase transitions in pharmaceuticals with the Linkam DSC450, Linkam Scientific Instruments, www.linkam.co.uk
- López-Mejías, V., Kampf, J. W. and Matzger, A. J. 2012. Nonamorphism in fufenamic acid and a new record for a polymorphic compound with solved structures. Journal of the American Chemical Society 134(24): 9872-9875.
- Reading M., Stacey D., 2015. A Thermal Analysis Technique That Combines Differential Scanning Calorimetry and Light Microscopy, American Laboratory (online: https://www.americanlaboratory. com/913-Technical-Articles/174891-A-Thermal-Analysis-Technique-That-Combines-Differential-Scanning-Calorimetry-and-Light-Microscopy/)
- Alhijjaj, M., Yassin, S., Reading, M., Zeitler, J.A., Belton, P., Qi, S. 2017. Characterization of Heterogeneity and Spatial Distribution of Phases in Complex Solid Dispersions by Thermal Analysis by Structural Characterization and X-ray Micro Computed Tomography Pharmaceutical Research 34(5), 971-89