Terahertz Time-Domain Spectroscopy of Poorly Soluble Pharmaceuticals
Illnesses and other health-related problems that people experience during their lives are often treated with pharmaceuticals. During the treatment drugs can be administered to patients in different ways, whereby oral administration of solid dosage forms is the most common one. For the success of suc...
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|Summary:||Illnesses and other health-related problems that people experience during their lives are often treated with pharmaceuticals. During the treatment drugs can be administered to patients in different ways, whereby oral administration of solid dosage forms is the most common one. For the success of such treatment, it is crucial that the orally administered drug completely dissolves in the gastro-intestinal tract, since only then the drug molecules can permeate into the systemic circulation and be delivered onto the site of action. Most of newly developed drugs are poorly soluble in aqueous media, which limits their bioavailability and therefore their potential for the patient treatment. Different strategies exist and are being explored for the improvement of the drug solubility. In this work we focus on the conversion of initially crystalline drugs into their amorphous state, which generally exhibits greater solubility compared to the crystalline counterparts. SmartFilms are a novel approach employing conventional paper to convert and maintain pharmaceuticals in the amorphous state and this way improving the solubility and bioavailability of the active pharmaceutical ingredients (APIs). However, the solubility advantage of formulations involving amorphous pharmaceuticals comes at a cost. Amorphous pharmaceuticals are inherently instable and tend to recrystallize, which can lead to insufficient and unpredictable patient treatment. Therefore, inspection methods are needed to control the solid state of pharmaceuticals in such formulations, preferably in a non-destructive way.
Terahertz (THz) time-domain spectroscopy (TDS) is a commonly used technique to perform spectroscopy in the so-called THz range, which is commonly defined as the part of electromagnetic spectrum ranging from 0.1 to 10 THz. Many pharmaceuticals show distinct absorption features in the THz range, which can be used for their identification. These spectral features do not only depend on the molecular structure but also on the crystalline structure. Therefore, different arrangement of the molecules within the crystal unit cell results in different absorption spectra. This enables a straightforward discrimination between polymorphs for many pharmaceuticals. Furthermore, amorphous materials, which lack the long-range order, typically show featureless continuous absorption in the part of the THz frequency range that can be effectively studied with a typical THz TDS system. This also means that crystalline pharmaceuticals can be easily distinguished from amorphous pharmaceuticals.
In this dissertation the focus was on exploiting the potential of THz-TDS for the investigation of amorphousness and crystallinity of APIs in smartFilms as well as tablets made from them. The obtained results underline the great capability of THz TDS for this task in case of many poorly soluble APIs, which show pronounced absorption features. By characterizing these absorption features of APIs, we developed a quantitative approach for assessment of the amount of amorphous and crystalline APIs in the tablets. Since THz-TDS is non-destructive, we were able to repeat the measurements on the same set of samples and this way directly investigate their stability in terms of inhibiting the recrystallization of the API. Thereby, it was found that the stability is API-dependent. Furthermore, the investigations revealed that smartFilms have a certain loading limit, up to which they are able to maintain an API amorphous. If this limit is exceeded, also initially amorphous API can recrystallize resulting in lower solubility and consequently lower bioavailability. By adding an additional carrier to the formulations, we were able to improve the loading limit as well as stability of such formulations. The obtained results reveal the applicability of THz-TDS for the inspection of amorphous formulations. As such, THz TDS can be seen as an alternative or complementary method to the more conventionally used methods for inspection of amorphous formulations such as x-ray diffractometry and differential scanning calorimetry.|
|Physical Description:||137 Pages|