Defining Drug Stability with Dissolution Testing

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Dissolution testing is an important aspect of drug development, allowing drug developers to determine the stability of a drug as well as providing in-vitro analysis of the drug’s behavior.

For solid oral dosage forms, dissolution testing is a requirement, necessary for detecting physical changes in an API as well as in the formulated product (1). Furthermore, including this analytical test early in the drug development lifecycle can allow drugmakers to optimize the drug’s release in a particular formulation.

With oral administration, drug absorption from a solid dosage form depends on the release of the active substance and its ability to be absorbed through the gastrointestinal (GI) tract of the patient. These two critical steps, solubilization and absorption, make in-vitro dissolution studies relevant predictors of a drug’s in-vivo performance.

In-vitro dissolution tests for solid oral dosage forms (e.g., tablets, capsules) are thus used to assess lot-to-lot drug product quality, guide the development of new formulations, and ensure continuing product quality and performance after changes in formulation, manufacturing processes, manufacturing scale up, and manufacturing site (1).

A major issue in drug development is the need to enhance the level of drug in the patient and the availability of the drug to be absorbed by the patient’s body to have the intended therapeutic affect for which it was made. The challenge has always been that, without correct optimization of drug levels and solubility, a drug may not have sufficient therapeutic effect. Whereas, too high drug levels and solubility can conversely lead to adverse events or toxicity in the patient. These factors make dissolution testing crucial to the drug development process.

For most dosage forms to be therapeutically effective, APIs must be absorbed into a body’s circulatory system, normally through the GI tract as mentioned earlier, for the drug to be transported to the targeted site. The dissolution and absorption process, therefore, contribute to the drug’s bioavailability, and it is in understanding this multi-step process that a proper in-vitro dissolution testing method can be developed.

Selection of appropriate in-vitro conditions, including media (e.g., solvent) and hydrodynamics, can simulate in-vivo conditions. However, conditions that are optimal for quality control purposes may not be applicable for establishing in-vitro/in-vivo correlation (IVIVC) (relationship between in-vitro properties and in-vivo response). This may make it necessary to establish two dissolution tests, one to meet development objectives and another to meet regulatory demands (3).

Common analytical methods

Dissolution tests should be robust and reproducible and should have the ability to discern changes in product performance. Typically, the characteristics of a drug’s dosage form dictate what specific dissolution testing technique should be used; however, industry testing standards are given by the United States Pharmacopeia (USP) (2).

USP describes four apparatus setups for dissolution testing techniques:

• Apparatus 1 comprises a vessel (can be covered), a motor, a metallic drive shaft, and a cylindrical basket.
• Apparatus 2 comprises the assembly in Apparatus 1 but adds a paddle element (blade).
• Apparatus 3 comprises a set of cylindrical glass vessels flat at the bottom, a set of glass reciprocating glass cylinders, inert fittings, nonsorbing, nonreacting screens, that cover the tops and bottoms of the glass cylinders, and a motor and drive assembly to move the cylinders.
• Apparatus 4 comprises a reservoir and pump for dissolution medium, a flow-through cell, and water bath (2).

Dissolution testing has also historically been used for quality control, in R&D applications to detect the effects of critical variables in the manufacturing process, and for comparative in-vitro/in-vivo studies (3).

The challenge of poor solubility

Poorly soluble drugs are another challenge to dissolution testing, particularly when the dosage form is meant to be an immediate-release formulation. Challenges to testing the dissolution of poorly soluble drugs include developing an appropriate test method, validating the method, demonstrating that the method is appropriately discriminatory, and dealing with the potential of an in-vivo/in-vitro relationship or correlation (4).

With poorly soluble drugs, the extent of drug release tends to be low, and it is common that the dosage from cannot be fully dissolved. Additionally, the rate at which drug is released is too slow, which hinders attainment of meaningful data from dissolution testing. Some approaches to improving the dissolution of poorly soluble drugs have been studied (4).

To start, increasing the volume of the dissolution solution helps to optimize the maximum dissolvable dose. Other approaches include changing the dissolution medium to another solution/compound that increases the solubility of the compound or reducing dissolution sink requirements. In addition, nonaqueous solvents can be used if appropriate. Media that has been known to improve saturation solubility include biorelevant media, surfactants with mixed micelles, and certain nonaqueous media, in addition to water.

Dissolution data for regulatory consideration

Dissolution testing has increasingly become an important tool in regulatory decision-making over a drug, especially generic drugs. The testing can be used to waive requirements for in-vivo bioequivalence studies, for example, in addition to its role in determining formulation development, in monitoring manufacturing processes, and its use as a quality control test. It also plays a role in predicting the potential for dose-dumping in the case of a modified-release drug product if taken with alcoholic beverages. In-vitro dissolution testing can reduce the regulatory burden on FDA as well as alleviate the need for human studies that may be unnecessary for generic drug development. At the same time, the quality of the generic drug product would not be impacted (5).

FDA’s guidance (1) on dissolution testing discusses the Biopharmaceutics Classification System (BCS), which is based on API solubility and permeability. According to the guidance, highly permeable drugs are classified as Case 1 for high solubility and Case 2 for low solubility APIs. APIs that have low permeability are classified as Case 3 for high solubility and Case 4 for low solubility. The classification serves to provide a basis for setting up in-vitro dissolution specifications for the test and can also provide a basis for predicting in vivo/in vitro correlation behavior.

The development of dissolution tests for a generic drug product must take into consideration the official methods and standards described by USP, while ensuring that the testing method is robust and can be reproduced in daily operations. The method should also be transferrable between laboratories. Finally, the test method must have the capability of distinguishing any changes in solubility behavior or drug properties that may affect the end product’s performance in vivo (5).

If there is an absence of an available USP method appropriate for the generic drug in question, a dissolution testing method can be developed following FDA guidelines or recommendations (6). In its guidance, FDA explains three categories under which dissolution specifications for generic products should be established:

• A USP drug product dissolution test is available
• A USP drug product dissolution test is not available, but a dissolution test for the reference listed new drug application (NDA) drug product is publicly available
• A USP drug product dissolution test is not available, and a dissolution test for the reference-listed NDA drug product is not publicly available (1).

As shown, setting dissolution specifications for generic drugs depends on whether or not an official compendial test exists for the drug product and what dissolution test was employed for the reference drug.

Even if an FDA-recommended method is not sufficient or fitting for a drugmaker’s specific API/product, then the generic drugmaker can develop its own dissolution method (5). In the end, FDA requires comprehensive dissolution testing data in the drug’s application as part of the generic drug review process.

References

1. FDA, Guidance for Industry, Dissolution Testing of Immediate Release Solid Oral Dosage Forms (CDER, August 1997).
2. USP, General Chapter <711>, “Dissolution,” USP29–NF24 (US Pharmacopeial Convention, Rockville, 2011).
3. Lubrizol Life Science Health, “In Vitro Dissolution Testing for Solid Oral Dosage Forms,” lubrizolcdmo.com/technical-briefs, March 9, 2020.
4. K. Gowthamarajan and S.K. Singh, Dissolution Technologies 17 (3) 24–32 (2010).
5. O. Anand, et al., AAPS J. 13 (3) 328 (2011).
6. FDA, “Dissolution Methods,” fda.gov, accessed July 20, 2020.

Article Details

Pharmaceutical Technology
Vol. 44, No. 8
August 2020
Pages: 47–48

Citation

When referring to this article, please cite it as F. Mirasol, “Defining Drug Stability with Dissolution Testing,” Pharmaceutical Technology 44 (8) 47–48 (2020).