Arguably, the biggest obstacle to achieving Active Pharmaceutical Ingredient (API) success in formulation development is API solubility. Solubility — the ability of a solute to dissolve in a solvent in a homogeneous manner — is essential to realizing the desired concentration of a drug in systemic circulation for an anticipated pharmaceutical response. Yet more than 40 percent of all New Chemical Entities (NCEs) have less than ideal solubility. Fortunately, today’s formulators have a range of excellent and steadily improving techniques available to provide acceptable solubility. The key to optimizing API success is having access to the right expertise and equipment.
The Importance of API Characterization
The standard practice of formulators is to begin with a thorough characterization of the physical and chemical characteristics of the API. It is vital that this step not be passed over, and yet this happens, often with disastrous consequences for both the project economics and timeline. Challenges on the path to solubility are the norm, not the exception. Only with a solid understanding of the characteristics of the API crystal structure is it possible to recognize the changes that will provide improved solubility. API characteristics often change with increased batch size, but with a complete understanding of the API characteristics, there is a baseline to compare these changes to, making it possible to pinpoint differences and make appropriate modifications. Without this basic knowledge, challenges that arise later are more difficult to evaluate and respond to resulting in unplanned changes to costs and timelines.
A thorough API characterization should include analyses such as determination of pH solubility profile, potential for polymorphs, pKa and particle shape/size.
Methods for Enhancing Solubility
Here are some of the tools available to the skilled formulator in assessing the viability of a poorly soluble API:
Physical Manipulation
If it is early enough in the development cycle, physical modifications to the API are possible. A salt form might be selected that has better solubility or an amorphous API might also be considered. Both of these modifications may be made during the synthesis. Increasingly, we are seeing the use of a spray-dried dispersion to create a stable amorphous powder.
Micronization can increase surface area to help dissolution of the API. Nanosuspension, modification of the crystal structure like polymorphs, co-crystallization and drug dispersion in carriers, solid dispersion, solid solutions and cryogenic techniques also fall under the physical manipulation category.
One of the newer technologies available is hot melt extrusion which can be used for waxy materials and/or to create a controlled-release formulation. In the hot melt extrusion process, an API is heated with the appropriate excipients to provide the desired characteristics. An extruder is used to force the material through an appropriately-sized screen, creating spaghetti-like strands. The resulting strands can be milled, blended with other excipients and compressed into a tablet.
Chemical Manipulation
Changing the pH can improve solubility, as can the use of buffer, derivitization, complexation and salt formation. The addition of surfactants or cyclodextrins may also lead to increased solubility.
The CDMO Advantage
Many pharmaceutical companies may find it beneficial to contract out formulation development involving API with solubility challenges. Contract development and manufacturing organizations (CDMOs) already possess a full range of equipment and the expertise necessary to deal with solubility challenges. Results are interpreted for the client and solutions to any identified problems are proposed. Hiring the necessary expertise and purchasing required equipment is rarely a cost effective solution for the pharmaceutical company. A CDMO is able to conduct the work more efficiently and at a lower cost.
It is difficult to predict what solubility challenges any particular API will exhibit. When dealing with solubility issues, there is no substitute for experience. In a pharmaceutical company, a formulator or analyst might work on one or two compounds for his or her career, dealing with only one or two formulations throughout that time period. A good CDMO would have a team of experienced formulators working together. Each formulator might focus on six to eight formulations a year, and as a team they would handle on average 25-30 formulations annually. These scientists deal with numerous types of molecules, all types of formulation processes, tablet sizes and dosage strengths which can range from less than 1 milligram to over 1000 milligrams.
CDMO formulation scientists are in the business of solving problems. Their experience allows for the development of formulations faster, utilizing less API. Companies will often ask the CDMO how much API is needed to develop a particular formulation. A good CDMO will reverse the question, asking how much API is available for the formulation development project. Once this is established, a development time/events plan can be put together to ensure that the project has the necessary clinical material available in time for clinical studies.
Equipment is also an important part of the formulation development process and can be an extensive part of the process as well. Equipment requirements are difficult to anticipate until you begin to characterize your API. Having a wide range of state-of-the-art equipment enables scientists to test multiple quantitative formulations and manufacturing processes quickly and cost effectively.
Excipient Selection
The formulation development process starts by identifying the optimal excipients for use with the API and dosage form of interest. The first consideration is to determine which excipients are going to be compatible with the API. Evaluating the molecular structure may immediately exclude some excipients due to known potential interactions between functional groups. An example of this would be the potential for a Maillard-type reaction to occur between lactose and APIs with a primary amine group. Another possible concern may be the amount of moisture present in some excipients or the potential for the excipient to modify the pH of the formulation.
Secondly, it is important to consider the type of formulation and route of administration. If it is a liquid formulation, a preservative and potential pH modifier may come into play. If the drug product is to be a controlled-release tablet, then appropriate polymers must be selected based on the type of release mechanism that will be utilized to control the API release. This could include technologies such as an erodible matrix or membrane-coated beads.
Thirdly, the manufacturing process needs to be taken into consideration. Will this be a direct compression formulation, or possibly a wet granulation?
Finally, solubility and possible dosage strength of the API should be evaluated. Excipients to increase solubility include surfactants such as the tweens or sodium lauryl sulfate. If there is an ideal pH for the solubility, pH modifiers could be considered. Water-soluble polymers can form complexes with the API to increase solubility also. Polyvinylpyrrolidone (PVP) is an excellent polymer used frequently for this purpose.
Lipid Based Formulations
Lipid based formulations can improve the solubility and/or the dissolution rate of an API. This might lead to consideration of a liquid-filled capsule approach to increase solubility. Lipophilic excipients such as Gelucires may also help improve solubility and bioavailability of the API. A self-emulsifying drug delivery system (SEDDS) formulation can improve solubility and possibly permeability. These approaches usually work best with APIs that are lipophilic and which readily go into solution with excipients such as olive oil.
Excipient Compatibility Studies
With so many possible excipients, the best approach is to begin with an excipient compatibility study which can provide a tremendous amount of information in a short time. Normally, the excipient compatibility study will evaluate ten to fifteen excipients. At this stage, the API is normally from a small batch of API which may or may not have the same physical characteristics of future batches of API. Prior to initiation of formulation development, it is not a problem if the characteristics of the API change. Ratios of excipients to API should be similar to what might be expected in the ultimate formulation. Using accelerated condition and room temperature storage conditions, the study is completed in two to three months.
From Excipient to Formulation Development
Depending on the timing needs of the project, formulation development work may begin as soon as one-month stability data is available.
Starting formulation development work with a simple process such as direct blend/compression can often be successful. If direct compression is not feasible, roller compaction would be evaluated as the next step. Wet granulation would be the last granulation approach explored.
CDMOs should be prepared to handle anything from an instant-release tablet, to a controlled-release bead. As an example, we have used cyclodextrins to successfully develop a pediatric liquid formulation. The use of cyclodextrins increased solubility significantly, producing a stable solution in the desired concentration. On another occasion, a client asked for a combination dosage form, but the two APIs were found to be incompatible when in direct contact. The solution was to coat each of the APIs separately. These coated beads could be combined without direct contact of the API’s, and the resulting blend was a stable dosage form.
Conclusion
API solubility is one of the most formidable obstacles to API success. There is no ‘if A then B’ playbook. Experienced formulators have the knowledge to engineer unique solutions for particularly troublesome APIs. The options discussed here are just some of those currently at the formulator’s disposal, but there is no substitute for experience in maximizing solubility/bioavailability in a timely and economic manner.
Dr. Paul Skultety joined the management team at Xcelience in 2008, bringing extensive experience in contract development and innovator companies. His broad drug development expertise and successful track record of developing new chemical entities from pre-IND to commercialization have made him an industry leader in the field of drug development and clinical solutions. He has nine U.S. formulation and composition patents and is author of numerous publications.