Formulation Development Options to the Clinic

Strategies for getting to Phase I quicker and saving API

By Paul Skultety, Ph.D.

Pharmaceutical companies are struggling to do more with less. Driven by pipeline productivity objectives and financial constraints, drug companies of all sizes are under pressure to reach critical milestones faster in spite of challenging molecular properties associated with their candidates, and with limited quantities of active pharmaceutical ingredient (API). The ability to work smarter has become a critical survival skill in order to move drug development candidates forward faster and to maximize the chance for success. Though not all are relevant for commercial scale, there are a host of formulation development options to consider that enable speed to first-in-human studies while conserving API and other resources. API in bottle, powder in bottle, API into capsule, and traditional formulations are all approaches worthy of consideration as possible formulation options for clinical supplies for a Phase I clinical trial. We shall explore considerations for prototype formulation development, formulation options for phase I studies, a prototype formulation approach, strategies to overcome poorly soluble compounds, liquid in capsule, and controlled release formulations.

API Considerations for Formulation Development

Provided the physical characteristics will not drastically change, formulation development projects may begin as soon as GLP-grade API is available. Most scientists understand the importance of setting chemical specifications and addressing chemical stability, but many fail to understand the benefit of assessing the physical characteristics and stability of their API early on. Solid state chemistry provides compound knowledge that helps maximize a drug development candidate’s chances for success and can help build and protect a sound intellectual property position. Chemical stability, sensitivity to moisture or light, pH solubility, polymorph identification, particle size, shape and distribution, flowability and physical stability: these are all important chemical and physical characteristics in API characterization. Once the dosage form approach — oral solid, oral liquid or parenteral — has been established, one needs to identify the appropriate technical leads for analytical and formulation development.

Formulation Options for Phase I Studies

For the oral dosing route of administration, there are four main dosage form options to consider for first-in-human studies.These are API in bottle, powder in bottle, API into capsule, and traditional formulation for tablets/capsules. All four options are utilized and each approach has associated advantages and disadvantages. These factors should be carefully considered prior to the selection of the appropriate option for each API.

API in Bottle

This approach is to directly weigh the API into the vial or bottle. This process eliminates the need for any excipients to be used, so there is no formulation development necessary. Analytical methods development is minimized as there is no need for additional methods work; the use of the API method is all that is needed. Stability is simplified, as there has been nothing added to the API and it is only in contact with the vial. This route minimizes the amount of API needed, as there is little loss of API in the manufacturing process, and it can support a wide range of dosage strengths; adding another strength simply requires changing the amount being weighed. In addition, due to the manufacturing process being only a weigh step, the physical characteristics of the API — such as poor flow or crystal structure — are not a problem.

The right solution must be selected for use in the clinic in order to provide a solution of the API. Most often this is water, but if the drug does not have sufficient solubility, a suspension may be used. If a suspension is the dosage form of administration, it is recommended that a rinsing study be conducted to make sure all of the API is delivered in the clinic at the time of dosing. It is also advisable to do some stability work on the solution or suspension. The Phase I clinic site may intend that the dose will be administered shortly after it is made, however there may be a time when something comes up and the prep will sit for an hour or two or more. A short-term stability study on the solution or suspension will save a lot of headaches, should the phone call arrive indicating that a delay in dosing has occurred.

Downfalls of this approach include additional clinic preparation time resulting from the need for someone to make the solution/suspension on-site, solubility limitations that may require large volumes of solution to be dosed or a suspension to be utilized, challenges associated with taste, patient inconvenience if the medication is taken home, and development of a matching placebo. One option for evaluating taste is using an electronic tongue, such as the Alpha M.O.S. Astree Electronic Tongue, which quantifies the bitterness of the API and assists in development of a suitable matching placebo for blinded clinical trials.

Powder in Bottle

Powder in bottle is a similar approach as API in a bottle that enables rapid progression into human clinical trials. This option supports a wide range of dosage strengths, eliminates API characteristics, does not require cleaning verification, and is a valid option for companies facing the challenge of limited API. When a bottle contains API and excipients, a minimum amount of developmental stability data are needed on both dry blend and reconstituted material. The advantage of this approach is that the possible bad taste may be masked by the addition of flavors to the powder blend.

Disadvantages of this approach include longer manufacturing time, clinic preparation time, patient inconvenience if the medication is taken home, and matching placebo. In addition, content uniformity can be an issue depending on the powder blend characteristics. More analytical method development is required to support the content uniformity testing. Depending on how the blend is manufactured, cleaning verification might be needed.

API into Capsule

API into capsule programs are a third means to provide a fast, cost-effective path to Phase I studies, allowing greater flexibility in dosing for clinic without resulting loss in quality. Overall development timelines may be reduced by as much as six months, since eliminating the need for excipients results in decreased formulation development and stability testing. Accordingly, the API into capsule approach eliminates the need for content uniformity testing and in some cases dissolution testing, resulting in time savings from reduced analytical method development and formulation requirements. Finally, development of a matching placebo is very straightforward.

Xcelodose® 600 S precision powder micro-dosing system. Photo courtesy of Capsugel

For most APIs, API into a capsule can be accomplished very quickly using automated systems, such as Capsugel’s Xcelodose® 600 S precision powder micro-dosing system. These APIs do not require a flow-aiding excipient or physical processing step. This approach is flexible and can provide a wide range of strengths without a lot of additional API being necessary. The yield of usable capsules is usually very high. Depending on the automated encapsulation equipment being used, cleaning verification may or may not be required.

This approach is suitable for both gelatin and hydroxy-propyl methylcellulose capsules, but compatibility of API with the capsule shell must be considered. Once the appropriate size and capsule type have been determined, lot release for clinical use is limited to one capsule type and API, and the creation of an approved batch record. It is important to stress that changes in the physical characteristics of the API should be kept to a minimum after the feasibility study, as this could alter the filling process on the encapsulation equipment.

Formulated Tablet/Capsule

Traditional formulation of solid oral dosage forms (tablets and capsules) may be initiated earlier, provided the chemical synthesis and physical representation of the API does not drastically change. The prototype approach for an oral solid tablet formulation starts with an excipient compatibility study as these provide a rational basis for identification of low risk excipients with physical and chemical compatibility to the API. A well constructed drug-excipient compatibility study typically involves between 15 and 20 excipients, and takes preformulation data, dosage strength, final dosage form, method of manufacturing, and animal study data into account, assigning a relative risk level to each excipient within a functional class.

For this approach, adding additional strengths will require much larger amounts of API. It is best to determine the dose range up front to determine how much work can be done with the available amount of API. For tablets, it is necessary to decide if one wants to develop a common blend or to keep the tablet size the same to minimize the placebo work needed for possible blinding purposes. Batch size requirements for the prototype formulations are between 100 – 300 grams and approaches can vary among direct compression, roller compaction and wet granulation. Granulation has many advantages including improved powder flow, improved compressibility, reduced amount of fines, ability to modify the density, improved content uniformity, and lastly the ability to control the segregation of excipients. It is usually best to develop two or three prototype formulations using different formulation approaches and/or excipients and put them all up on prototype stability. This will help to ensure an acceptable formulation is ready for the start of the Phase I trial.

Critical success factors for prototype formulation development vary by dosage strength. For a high dose (> 250 mg), critical API characteristics include flowability, compressability, and availability of material. For midrange doses (25 mg – 250 mg), critical characteristics include availability and flowability. For a low dose (< 25 mg), handling procedures and solution stability are API characteristics, in addition to concerns regarding content uniformity. Each prototype formulation is placed on stability in order to evaluate both physical and chemical characteristics over time. Criteria for the evaluation and selection of the optimal formulation includes ratio of excipients, flow characteristics, hardness versus force, particle size granulation and dissolution profile (pH dependency of release rate).

There are two big advantages to this approach over the other three discussed. It is faster to start a Phase II trial with an acceptable dosage form that can be modified into a commercial formulation, and there is less concern about having to do a bridging study from the formula that was utilized in the Phase I study.

The disadvantage of this approach is that it will take much longer to develop an acceptable formulation. There will be the cost of the additional analytical support for methods development, including a cleaning verification method and stability studies. Dissolution is now needed for release of the clinical supplies and for the stability testing. There will be less flexibility in providing different dosage strengths and the amount of needed API has increased several fold. Depending on the strength(s) being developed, content uniformity might be a concern. The particle size and shape of the API will potentially play a much bigger role in how robust the manufacturing process will be.

Considerations for Manufacture of Phase I Clinical Supplies

Once the optimal formulation approach is selected, it is time to develop the clinical manufacturing plan. Batch size requirements for a typical Phase I clinical supply range from 250g to 1kg of powder blend or API, depending on which formulation approach is carried forward. The goal is to end up with approximately 5,000 – 10,000 dosage units. This amount includes enough to handle retain samples, release testing and stability.

For tablets and capsules, it is important that the selected formulation is robust enough to meet the in-process specifications for tablet hardness and be able to maintain the acceptable weight range. In addition, the formulation should be able to meet release specifications for dissolution, disintegration, assay and content uniformity.

Overcoming Poor Solubility For Oral Solid Dosage Forms

Over the past decade, formulators have faced unprecedented challenges with drugs of poor solubility. One-tenth of marketed drugs have solubility problems, more than one-third of drugs in the pipeline are poorly soluble, and nearly two-thirds of drugs from synthesis stage have low solubility [<0.1 mg/mL].¹Conventional formulation and process strategies to overcome poor solubility have included the use of water soluble excipients, API micronization, pH modifiers, or solubilizing or wetting agents. Alternate processing approaches include the addition of an aqueous granulating solution which contains a wetting or solubilizing agent, using high shear homogenization to reduce the API to nanoparticles, potentially altering the API characteristics by dissolving API into hydroalcoholic/alcoholic granulating solutions, the formation of solid dispersion or hot melt extrusion, the use of complexing agents such as cyclodextrins, spray drying the API with wetting or solubilizing agents, or liquid fill into hard gelatin capsules.

The “liquid filled in hard shell capsule” option eliminates poor flow, bad taste, concerns about content uniformity and physical characteristic concerns of the API. This removes the need for inclusion of a flow aid, sweetener or a flavorant in the formula. Relative to the traditional dosage formulation development process, these aspects present lesser challenges and decrease the time and API requirements, also eliminating the need for taste evaluation or a taste panel. In addition, the elimination of taste-matched placebo development for blinded clinical trials is a big advantage, and supports the time stringent nature of the projects. Capsugel’s CFS 1200 is one example of automated instrumentation that enables standard liquid filling using LiCaps® capsule and Liquid Encapsulation Microspray Sealing (LEMS®) technology².

When utilizing the liquid in capsule option, the foremost challenge is solubilizing the API in a favorable solvent system. The wide variety of marketed excipients forces formulators to understand the basic nature of the drug and to gain familiarity with the various excipients in order to make the optimal selection. Bioavailability enhancers are also available if needed. API considerations include dose requirements, melting point, drug substance stability, and excipient selection. For liquid filled capsules, corn oil, castor oil and sesame oil are recommended excipients. For semi-solids, gelucires and cremophor are proposed excipients.

Controlled Release Formulations in Phase I

A general approach for development of controlled release formulations involves identifying the desired product characteristics and estimation of dose range. This information can be used for defining the optimal dosage form (tablet, capsule or multiparticulate). There are a variety of controlled release systems for consideration: diffusion controlled, erodible, osmotic control and swelling. Pharmacokinetic considerations can be used for estimating the in vitro release rate (8- or 24-hour release).

A typical sustained release development plan can include the development of several prototype formulations, which may include different release mechanisms. These should be placed on stability to evaluate them for any potential problems. Ideally at least three different release rates will be used in the Phase I study: the target release profile, and then one faster and one slower than the target. This will allow for the start of development of an in vitro/in vivo correlation.

Companies are faced with a number of excellent options for possible formulation approaches to take into Phase I clinical studies.It is important to try to make the optimum formulation choice that will give the API the best chance of success. In addition, the most critical factors for development must be evaluated. There is no one right formulation approach that will fit every API. A company must evaluate the advantages and disadvantages of each approach to determine if it is the need to save time, save money, or conserve available API that will determine which option is the best for their compound.

References

1 T. E. Cole, “Liquid Filled and Sealed Hard Gelatin Capsules,” Capsugel Library (2000)

2 Xcelodose and LEMS are registered trademarks of Capsugel

Paul Skultety, Ph.D. is director, Pharmaceutical Development Services, at Xcelience, LLC, a provider of drug development and manufacturing solutions for virtual, specialty and large pharmaceutical companies. The author would like to acknowledge the help of Kim Black-Washington, whose assistance was invaluable in preparing the manuscript.