Solubility and Dissolution Rate of Active Pharmaceutical Ingredients: Dissolution Media and Effect of Enhancers
[eng] The present doctoral thesis is focused on the effect of pH, enhancers and biorelevant media in the Solubility and the Dissolution Rates of some selected acidic active pharmaceutical ingredients (API). Because of the effect of these physicochemical parameters in the bioavailability of drugs and...
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| Format: | doctoral thesis |
| Status: | Published version |
| Publication Date: | 2021 |
| Country: | España |
| Institution: | Universidad de Barcelona |
| Repository: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/177763 |
| Online Access: | https://hdl.handle.net/2445/177763 http://hdl.handle.net/10803/671762 |
| Access Level: | Open access |
| Keyword: | Solubilitat Solucions (Química) Excipients Química farmacèutica Solubility Solution (Chemistry) Pharmaceutical chemistry |
| Summary: | [eng] The present doctoral thesis is focused on the effect of pH, enhancers and biorelevant media in the Solubility and the Dissolution Rates of some selected acidic active pharmaceutical ingredients (API). Because of the effect of these physicochemical parameters in the bioavailability of drugs and their pharmacological action, deepen the knowledge on the factors affecting the dissolution properties is of paramount importance in the drug development process. Solubility and dissolution rates are examined in different aqueous solutions and buffering systems, accounting for the pH values of main interest in the gastrointestinal tract (2.0, 5.8 and 6.5), together with dissolution media that simulate intestinal fluids in fasted (FaSSIF) and fed states (FeSSIF). It is also determined in these media and discussed the effect of some excipients intended as dissolution enhancers, such as cyclodextrins, polyvinylpyrrolidones and hydroxypropylcellulose. Finally, differential scanning calorimetry was used to identify solid-solid interactions between excipients and APIs. As a complementary investigation, this thesis also presents a comparative study of the reference shake-flask and potentiometric CheqSol methods for the determination of solubility, including APIs with different acid/base properties (acidic, amphoteric and basic). The study confirms that solubility is pH dependent, and an accurate pKa determination of the drugs is needed to detect the presence of concurrent aggregation or complexation reactions affecting the amount of compound dissolved. As expected, the addition of excipients increases the solubility of APIs, but in different degrees depending on the drug, excipient, and pH conditions. Solubility in simulated intestinal fluids is generally improved, and the addition of excipients might increase, diminish or even cancel the enhancement, depending on the matrix formed. Interestingly, the factors improving the solubility of an API do not necessarily enhance its dissolution rate. The release of the drug from its compressed solid form (tablet) is a complex process, involving an aqueous boundary layer between the solid and the bulk solution. The results of this thesis point out the need of systematic and detailed dissolution studies in the step of pharmaceutical formulation, as long as the enhancement produced by a particular excipient in a singular dissolution medium can be characteristic of an individual API, and these results cannot be uncritically extended to other drugs. |
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