Solving solubility issues in modern API’s
Oshrat Frenkel, Associate Director, Pre-Formulation, TAPI Global R&D
The latest generations of chemical entities currently under development as well as those that are just entering the market are less soluble than their predecessors. TAPI has developed new techniques to overcome these issues. In this article Oshrat Frenkel, the Associate Director of Pre-Formulation at TAPI, explains the techniques developed by TAPI to optimize API with low solubility and better characterize it to enhance formulation development.
Low solubility and low permeability, a growing feature of modern API’s
Today between 40%, and up to 70% of New Chemical Entities (NCE) are characterized as having low aqueous solubility (based on different estimates). Some of these NCEs are also considered to have low permeability. Thus, these APIs are defined by the FDA, Biopharmaceutical Classification System (BCS ) II and IV.
API’s that are classified as BCS Class II have low solubility and high permeability, dissolution is considered as the rate-limiting step to efficacy/API performance upon administration.
BCS class IV API’s have both low solubility and permeability, dissolution might also have a major impact on the API profile. TAPI, as a world leader API-focused R&D company is fully committed to the future success of our customers by addressing and countering these challenges through formulation development.
Why TAPI is developing new dissolution capabilities
TAPI has established in-house capabilities of dissolution methodology development for API testing. TAPI R&D teams have expertise in both intrinsic and dissolution profile testing, which starts early in an API’s development. When conducting dissolution studies this allows our researchers to optimize API crystalline form selection and to fine-tune the solid-state properties of the API.
The development of a dissolution procedure involves selecting the dissolution media(s) at the relevant pH and ionic strength, apparatus type and hydrodynamics appropriate for the API product. API screening with aqueous media is done in the physiological range of pH 1.2 to 6.8 at different ionic strength. For low solubility APIs in aqueous media throughout the pH range, the addition of surfactants may also be tested.
Technically, we most commonly use USP Apparatus 2 (paddle) dissolution equipment. Obviously dissolution testing of an API requires an adequate analytical method development, which is usually HPLC-UV based. API properties such as pKa, solubility as a function of pH/surfactant concentration, particle morphology and size, surface area, polymorphism and stability, are likely to affect the in vitro dissolution behavior and should be evaluated as part of method development. Clearly, there are additional method parameters and nuances that should be considered during API dissolution method development.
API dissolution profiling when employed can help our customers to better choose their drug substance and it’s specific grade. This specific input can be a part of decision-making during consideration of the formulation strategy. Naturally TAPI will work closely with our customers to offer advice and expertise during the R&D phase.
Dissolution analysis and characterization
As API vendors, dissolution testing helps us characterize API alternative salts, potential solvates and solid dispersion. TAPI team characterized a new potential co-crystal of a blockbuster low soluble API. Co-crystals are multicomponent crystals of, at least two molecules (API+coformer) combined in a stoichiometric ratio. Co-crystals have shown efficacy on improving apparent aqueous solubility and dissolution profile of poorly water-soluble APIs, as well as other properties important for API development including; hygroscopicity, taste, and API process-ability.
In depth dissolution analysis concluded that one specific co-crystal in a specific stoichiometric ratio had beneficial properties of intrinsic dissolution, dissolution profiling and apparent solubility. Providing our customer a unique drug substance with excellent biophysical properties in a highly competitive generic market, was the consequence of adding dissolution testing to this specific API’s development. Clearly, dissolution profiling and specifically intrinsic dissolution testing is providing meaningful insights for the pharma researchers developing a generic drug product formula of a challenging API.
New possibilities in drug development
The know-how of our scientists in designing an applicable dissolution method while taking into account API properties, and analytical aspects, is contributing to our excellence in drug substance development. Appropriately designed dissolution method for a challenging API drug substance is in fact, shown to accelerate generic drug development. Opening new opportunities for future developments.
A short case study
In one specific case TAPI team studied 3 different crystalline forms of a BCS class IV API. This specific API was a first-in class formulated in a tablet by the innovator using roller compaction dry formulation process. The API aqueous solubility was low and not pH dependent. TAPI’s team evaluated two optional crystalline forms as well as an amorphous. While performing thermodynamic solubility testing all 3 forms had similar solubility.
When evaluating the intrinsic dissolution properties and the dissolution profile it became clear that indeed, the amorphous intrinsic dissolution rate was approximately 4 times greater than the crystalline forms. XRD analysis of various samples of amorphous API actually showed a conversion to the most stable crystalline polymorph takes place in just over 2 hours.
Particle size reduction, a success story
For the sake of in-depth analysis of particle size reduction and batch-to-batch variation in scale-up dissolution may be very helpful tool in R&D. Our team evaluated three different grades of a specific crystalline form of an API. Because the API had extremely low aqueous solubility in physiological pH range it was expected that micronization and API particle size of d(90)< 20µm will render increased surface area and therefore increased apparent solubility. Moreover, the high impact implemented through micronization may result in increased amorphous content, which may result in increased apparent solubility. When dissolution profiling was performed it became clear that micronized API was much less dispersible. This may be attributed to API aggregation that resulted in reduced surface area. More gentle milling process provided bigger particle size but less aggregated API, which had beneficial dissolution profile. This milling and not micronization was selected as routine process for particle size reduction.
About the author
Oshrat Frenkel is Associate Director, Pre-Formulation for TAPI Global R&D and holds a Ph.D. in Pharmaceutical Sciences from Hebrew University and an MBA from the Interdisciplinary Center.