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Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.
Understanding the API, delivery mechanism, and excipient functionality is essential to solving drug solubility challenges.
Dissolution in the intestinal tract is an essential first step in the delivery of most oral solid-dosage drugs. A high percentage of drug candidates today are, however, considered to be poorly soluble according to the Biopharmaceutical Classification System (BCS). Formulators are challenged to develop delivery mechanisms to overcome these solubility issues. Many excipients can enhance solubility as well. The challenge is to select the right ones for the specific API and dosage form.
A diverse array of excipients is used for solubility enhancement, including cellulosics, vinylpyrrolidones, acrylates, modified or copolymer variants of these chemistries, and various lipids such as triglycerides. Poorly soluble APIs can also be formulated with carriers such as cyclodextrins to form complexes that can enhance solubility and bioavailability.
Each of these excipient classes are capable of drug/polymer interactions that stabilize the compound in the desired state (e.g., amorphous state) and deliver it as intended, according to Kevin O’Donnell, R&D manager in pharma excipients at DowDuPont Specialty Products (DuPont) Division. “With the exception of controlled-release systems, these polymers will also be hydrophilic, possibly with pH-dependent dissolution, to improve wettability of the final formulation of the often highly hydrophobic APIs,” he explains.
Recent excipient introductions into the pharmaceutical market have been focused on overcoming processing limitations, because the formulation of poorly soluble compounds typically requires an enabling manufacturing technology, according to Paula Garcia-Todd, global strategic marketing manager for drug delivery technologies at DuPont Nutrition & Health.
The rationale for selecting the appropriate excipients for solubility enhancement should be primarily driven by the chemical structure and physico-chemical properties of the API and the target drug load, which together lead to the desired final dosage form, according to Sanjay Konagurthu, senior director of science and innovation in the pharma services group, part of Thermo Fisher Scientific.
Typical API properties used for selecting the appropriate excipients include aqueous solubility, LogP, LogD, pKa, melting point, glass-transition temperature, organic solubility, thermal stability, precipitation kinetics, chemical stability, and others.
For example, O’Donnell notes that if the API is not soluble in organic solvents, it is likely that a fusion technology such as hot-melt extrusion (HME) will be used. In that case, excipients amenable to extrusion will be the first to be evaluated. Conversely, if the API is thermally unstable, excipients that are soluble in the same solvents as the API will be evaluated for spray drying.
“A couple of the most fundamental considerations for developing robust formulations are ensuring that the API has sufficient solubility and stability in the solubility-enhancing excipients. These are the critical properties to overcome a solubility hurdle of the API,” adds Ronak Savla, scientific affairs manager, Catalent.
Ultimately, formulation choices for excipients are primarily driven by the type of enabling technology used for solubility enhancement, according to Konagurthu. “We need to ensure we choose the right excipients for maintaining the physical and chemical stability of the intermediate(s) as well as the final dosage form,” he says.
Lipid-based drug delivery systems (LBDDS) are one of the most widely used technologies for solubility enhancement, according to Savla. LBDDS can contain different combinations of oils (triglycerides or mixed glycerides), water-soluble surfactants (e.g., different forms of castor oil and polysorbates), water insoluble surfactants (e.g., oleic acid), and co-solvents (e.g., ethanol, PEG400, and propylene glycol).
“These excipients solubilize drugs or form emulsions. Therefore, in addition to purity and safety of the excipients, the most important attributes to consider during LBDDS development are the solubility and stability of the drug in the formulation and the minimization of drug precipitation upon contact with gastrointestinal fluid,” explains Savla.
Amorphous solid dispersions (ASDs) are increasingly used for solubility enhancement. In HME and spray-drying, the API is distributed throughout a polymer network, maintaining the API in a higher-energy amorphous state with greater solubility than its preferred lower-energy crystalline state. “To ensure stability of ASDs, the polymer should not only be compatible with the drug but also be miscible and enhance the supersaturation of the API in aqueous media,” Savla observes.
A wide range of polymers are used in ASDs, including cellulosics, polyvinyl derivatives, and polymethacrylates. Hygroscopic or acidic polymers that might lead to hydrolysis or acidic degradation are an exception. Various additives such as surfactants, plasticizers, and permeation enhancers are also often employed by formulators.
The dosage form itself will impact the choice of excipients as well. For oral solid-dosage forms, Garcia-Todd notes that the permitted daily dose of an excipient and the physical properties of the excipient (e.g., many lipids may not be suitable for tablet formulation) must be considered. For non-oral routes of administration, such as implantable formulations, she adds that regulatory or toxicology limitations may exist for an excipient that limits or prevents its use.
Formulation requires time and resources to create and test different formulations in the laboratory. Modeling and simulation tools hold the promise to improve speed and reduce costs by helping formulators simulate API-polymer interactions and focus their experiments on the polymers that have the most promise, according to Savla. He does note, however, that these modeling and simulation technologies are still in their infancy and there needs to be a continued effort to build the dataset for these models and validate them against in-vitro experiments.
For Garcia-Todd, modeling and simulation are already useful to some extent. “While modeling and simulation can be useful for eliminating certain excipient classes during excipient selection, they are not yet to the point of identifying a single best option. Often, these systems will identify a number of excipients that are most likely to be successful but it is then up to the formulator to test the set and identify which is indeed most capable of improving drug solubility for a given API,” she says.
Konagurthu, on the other hand, notes that the speed and performance of computational modeling methods using quantum mechanics (QM) and molecular dynamics (MD) has significantly improved, allowing for rapid in-silico screening of drugs in more complex environments. “To further improve success rates and reduce development time and cost, early consideration of the drug delivery method and formulation approaches should begin in parallel with drug discovery and development programs,” he asserts.
Thermo Fisher is actively leveraging modeling and simulation tools for excipient selection. The company has developed a novel in-silico approach/platform for identification of the appropriate solubilization technology and excipient selection for solubility enhancement, according to Konagurthu. The platform is designated as Quadrant 2 and is an agnostic approach toward formulation selection of excipients based on computer algorithms that use a combination of calculated descriptors and available experimental physico-chemical properties.
“Excipient selection and drug loading is accomplished by calculating descriptors, energies of interactions from QM and MD simulations combined with machine learning. These provide the input to an algorithm that provides a rank ordering of recommended excipients and drug loading options,” Konagurthu explains.
Thermo Fisher uses these simulations in the early phases of the development process to rapidly identify candidate excipients for drugs, predict key experimental properties of the formulations, and determine drug loading and formulation stability. Notably, the company has validated its models with experimental data for more than 175 compounds to a predictive accuracy of greater than 80%, according to Konagurthu.
Many companies have their own unique protocols for excipient screening/selection for solubility enhancement formulations. “While methods will vary, the common goals will include (for ASDs), identifying the excipients most capable of holding the drug in the amorphous state (e.g., film casting and looking for residual crystallinity); identifying which of those are capable of generating strong supersaturation and maintenance thereof; identifying the potential drug load in the strongest candidates; and analyzing for potential incompatibilities. Additional steps may include evaluation of excipient properties of each candidate excipient in the intended manufacturing method,” O’Donnell explains.
At Catalent, the first step is screening API solubility, stability, and potential solid-state changes in a panel of common excipients used in FDA-approved products. Based on these results, formulation prototype development with other ingredients (surfactants, co-solvents, etc.) is undertaken. “It is important to keep in mind that the amount of excipient in the formulation is under the maximum allowable potency per dose,” Salva notes.
Thermo Fisher first uses its Quadrant 2 platform to select an available list of solubility enhancement technologies suitable for the API. The algorithm then identifies candidate excipients for each technology type and predicts factors such as maximum drug loading, stability, and dissolution performance for numerous different excipients. “Based on these results, a significantly reduced number of candidate excipients is generated. The top five to six are selected for experimental feasibility screening using small amounts of API (<1g),” Konagurthu says.
“Every API is different, and unfortunately there is no silver bullet that is effective for all drugs,” Garcia-Todd asserts. “With each compound, the formulator must identify the best enabling technology and the best excipient concurrently, and often these do not match. Finding the proper balance of performance and manufacturability is crucial early in development to ensure a drug product is effective and does not fail because it cannot be made,” she says. Adds Konagurthu: “The most challenging aspect is to reduce the number of excipients to a manageable level and have a high probability of improving the solubility and bioavailability.”
What will help ensure success? “First, be material agnostic,” says O’Donnell. Just because an excipient worked in the past does not mean it will be the best choice in all cases. “Second,” he continues, “understand the limitations of your excipients in manufacturing technologies: do not try to force fit an excipient into a technology. Third, solubility enhancement does not guarantee bioavailability enhancement; advance more than one formulation into in-vivo studies.”
For Savla, because every drug is unique, it is important to comprehensively characterize the API to understand the challenges (e.g., poor solubility in acidic conditions) and develop potential formulation. It is also important to recognize that excipients work through different mechanisms in different enabling technologies. He also notes that some amount of experimentation is required.
The first step to take, according to Konagurthu, is identifying the appropriate enabling technology for solubility enhancement based on the API’s physico-chemical properties. Next, it is important to avoid excessive time-consuming empiricism by having a rational selection and screening strategy for excipient selection without relying on “trial-and-error” approaches. Ultimately, he says the goal is to make sound decisions based on balancing the aspects of bioavailability, manufacturability, and stability to develop a robust, commercializable drug product.
Vol. 43, No. 3
When referring to this article, please cite it as C. Challener, “Strategic Screening for Solubility Solutions," Pharmaceutical Technology 43 (3) 2019.