Cyclodextrins (CDs) are cyclic oligosaccharides composed of D-glucopyranoside units linked by glycosidic bonds. Their main property is the ability to modify the physicochemical and biological characteristics of low-soluble drugs through the formation of drug:CD inclusion complexes. Inclusion complexation requires that host molecules fit completely or partially within the CD cavity. This adjustment is directly related to the physicochemical properties of the guest and host molecules, easy accommodation of guest molecules within the CD cavity, stoichiometry, therapeutic dose, and toxicity. However, dosage forms may achieve a high volume, depending on the amount of CD required. Thus, it is necessary to increase solubilization efficiency in order to use smaller amounts of CD. This can be achieved by adding small amounts of water-soluble polymers to the system. This review addresses aspects related to drug complexation with CDs using water-soluble polymers to optimize the amount of CD used in the formulation in order to increase drug solubility and reduce dosage form volume. Uniterms:Cyclodextrins. Ternary complexes. Drugs/complexation. Water-soluble polymers/use. Drugs/ solubility. Inclusion complexe.Ciclodextrinas (CDs) são oligossacarídeos cíclicos, compostos por unidades D-glicopiranosídicas ligadas entre si por meio de ligações glicosídicas e sua principal propriedade está na capacidade de alterar as características físico-químicas e biológicas de fármacos com baixa solubilidade por meio da formação de complexos de inclusão fármaco:CD. Para a formação dos complexos de inclusão a molécula hospedeira necessita ajustar-se total ou parcialmente no interior da cavidade da CD, onde este ajuste está diretamente ligado a propriedades físico-químicas da molécula hóspede e hospedeira, facilidade de alojamento da molécula hóspede no interior da cavidade da CD, estequiometria, dose terapêutica e toxicidade. No entanto, as formas farmacêuticas podem atingir um elevado volume, em função da quantidade de CD requerida, sendo necessário aumentar sua eficiência de solubilização para que seja possível utilizar menores quantidades das mesmas. Isso pode ser obtido com a inclusão de pequenas quantidades de polímeros hidrossolúveis ao sistema. Nessa revisão, são abordados aspectos relacionados à complexação de fármacos com ciclodextrinas empregando-se polímeros hidrossolúveis para otimização da quantidade de CD utilizada na formulação, com a finalidade de aumentar a solubilidade do fármaco e reduzir o volume das preparações.Unitermos: SCiclodextrinas. Complexos ternários. Fármacos/complexação. Polímeros hidrossolúveis/ uso. Fármacos/solubilidade. Complexos de inclusão.

The Biopharmaceutics Classification System (BCS) is a tool that was created to categorize drugs into different groups according to their solubility and permeability characteristics. Through a combination of these factors and physiological parameters, it is possible to understand the absorption behavior of a drug in the gastrointestinal tract, thus contributing to cost and time reductions in drug development, as well as reducing exposure of human subjects during in vivo trials. Solubility is attained by determining the equilibrium under conditions of physiological pH, while different methods may be employed for evaluating permeability. On the other hand, the intrinsic dissolution rate (IDR), which is defined as the rate of dissolution of a pure substance under constant temperature, pH, and surface area conditions, among others, may present greater correlation to the in vivo dissolution dynamic than the solubility test. The purpose of this work is to discuss the intrinsic dissolution test as a tool for determining the solubility of drugs within the scope of the Biopharmaceutics Classification System (BCS).

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Hypochlorhydria is a condition where the production of hydrochloric acid in the stomach is decreased. As a result, the intragastric pH is elevated. This condition can be due to a series of causes, such as disease (gastric mucosal infection caused by Helicobacter pylori and is prominent in AIDS patients), ethnicity, age and also the use of antisecretory agents. This may significantly impact the absorption of other drugs that have pH-dependent solubility, such as ketoconazole, a weak base. Within this context, the purpose of this study was to demonstrate how GastroPlusTM – a physiological based software program- can be used to predict clinical pharmacokinetics of ketoconazole in a normal physiological state vs. elevated gastric pH. A simple physiologically based pharmacokinetic model was built and validated to explore the impact that different physiologic conditions in the stomach (hypochlorhydria, drug administered with water and Coca Cola®) had on ketoconazole’s bioavailability. The developed model was able to accurately predict the impact of increased pH and beverage co-administration on dissolution and absorption of the drug, and confirmed that complete gastric dissolution is essential. Particle size only mattered in hypochlorhydric conditions due to the incomplete gastric dissolution, as its absorption would depend on intestinal dissolution, which corroborates with previous studies. Therefore, in silico approaches are a potential tool to assess a pharmaceutical product’s performance and efficacy under different physiological and pathophysiological states supporting the assessment of different dosing strategies in clinical practice.