Techniques to Enhance Drug Solubility

Solid preparations for oral administration for children have the advantages of convenient carrying and good stability, but for children, they are prone to dysphagia. The liquid dosage form for oral administration for children not only has benefits like large dispersion and fast absorption, but also can improve the bioavailability of some drugs, which has a greater development prospect and clinical application value.

However, there are some technical difficulties that hinder the development of children's oral liquid preparations. Poor solubility of the drugs is one of these difficulties and is worth deeper exploration.

In the process of preparing drugs into liquid preparations, a common problem is that most drugs are poorly soluble in water. According to statistics, among more than 200 listed oral drugs, insoluble drugs account for about 40%. The problem of poor water solubility of drugs not only directly affects the absorption and bioavailability of drugs in the body, but also greatly increases the volume of liquid taken, which will increase the swallowing pressure of children to a certain extent. To solve this problem, several techniques can be employed.

Solubilization technology

At present, most of the methods for improving the solubility of drugs on the market are mainly drug solubilization methods, including ①pH adjustment method: suitable for some weakly acidic and weakly basic drugs, by adjusting the pH value to increase the solubility of the drug; ②mixed solvent method: add a certain proportion of organic solvents (ethanol, glycerol, ethylene glycol, polyethylene glycol, etc.) to the aqueous solution to maximize the solubility of the drug; ③surfactant solubilization method: commonly used in suspensions and emulsions, using the amphiphilic nature of the active agent to solubilize the drug.

Nanocrystals technology

Due to the toxicity of solvents and surfactants, traditional drug solubilization methods are limited, so some drugs cannot achieve sufficient dosage concentrations. In recent years, drug nanocrystals are a new type of nano drug delivery system. Through certain means (mainly media grinding method, high-pressure homogenization method, etc.), drug particles can be highly dispersed in the dispersion medium to form nanometer-level drug crystals. Because nano-level drug crystals have a large specific surface area, according to the Ostwald-Freundlich and Noyes-Whitney formulas, this technology can effectively increase the saturated solubility of the drug, greatly improve the bioavailability, and reduce the dosage of the drug to a certain extent, thereby reducing the occurrence of adverse reactions.

Aprepitant is mainly used to prevent nausea and vomiting for children during chemotherapy. It belongs to class IV drug in the Biopharmaceutical Classification System (BCS) and has the characteristics of poor water solubility and poor permeability. Therefore, the development of oral liquid preparations for aprepitant is difficult. In December 2015, a dry suspension of aprepitant was developed by a pharmaceutical company for pediatric patients from 6 months to 12 years old and was approved by the FDA for marketing. In this formulation, the media grinding method is used to prepare aprepitant drug nanocrystals, so that the particle size of the drug crystals can be reduced to less than 250 nm, and low-viscosity hydroxypropyl cellulose and sodium laurate sodium sulfate are used as the surface stability of the nanocrystals, and then further prepared as a dry suspension. This new drug not only effectively solves the problem of water solubility, but also improves the average bioavailability to 60% to 65%.

Self-microemulsifying technology

The self-microemulsifying drug delivery system (SMEDDS) is a uniform transparent solution composed of oil, surfactant and co-surfactant or a small amount of water. The drug is dissolved and dispersed in an oil phase medium, and after oral administration, the drug-containing self-microemulsifying system will spontaneously disperse in body fluids under gastrointestinal peristalsis to form an O/W type microemulsion. This technology can not only effectively increase the solubility and bioavailability of the drug, but also the single oil phase system can effectively increase the stability of the liquid formulation.

In recent years, self-microemulsion preparations have also been developed in the field of children's medicine. In 2007, a pharmaceutical company developed ibuprofen liquid capsules. The capsule is loaded with a self-microemulsification preparation containing ibuprofen, and its prescription ingredients are all FDA-approved safer pharmaceutical excipients, with medium chain triglyceride (MCT) as the oil phase, lecithin and Glyceryl stearate as a surfactant, PEG600 as a co-surfactant, and ascorbyl palmitate as an antioxidant. It is worth noting that compared with the traditional ibuprofen suspensions, ibuprofen self-microemulsion has better stability. The disadvantage is that it still needs to be stored in soft capsules for preservation and use.

Equipped with a cGMP-compliant lab and state-of-the-art analytical instruments, CD Formulation is capable of providing valuable insights in all aspects of pharmaceutical formulation development and dosage form optimization. In addition, the company can also provide analytical services, namely solubility analysis, for a variety of dosage forms to explore their dissolution profiles in various solvents, including inorganic solvents with different pH values, organic solvents, simulated intestinal juice or gastric juice, and other solvents.