四色AV

Although the majority of new drug candidates suffer from poor solubility and bioavailability,听oral solid dosage forms听remain the preferred route of administration due to their ease of use and convenience for patients and caregivers. In recent years, numerous drugs formulated as amorphous solid dispersions (ASDs) have been successfully commercialized, confirming the effectiveness of these technologies for enhancing the dissolution of challenging APIs.

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Addressing Solubility Issues

Lead optimization during drug development does not typically address dissolution and bioavailability performance under physiologic conditions.听As a result, a large percentage of pipeline candidates exhibit poor water solubility and low bioavailability. The challenge is to develop听formulations and delivery mechanisms for these drug substances that enable oral administration, which remains the most desirable dosage form due to its generally lower cost of production, the preference of patients and caregivers for oral medications and overall higher compliance rates.

Benefits of ASDs

Enhancement of dissolution, solubility and bioavailability for poorly soluble APIs can be achieved using a number of different approaches, including听particle size reduction听(e.g., micronization and nanomilling), salt or cocrystal formation, lipid-based self-emulsification and the formation of ASDs.

For many poorly soluble drugs, preparation in an amorphous rather than a crystalline state can lead to improved dissolution profiles and enhanced bioavailability, as amorphous compounds lack long-range order. However, amorphous compounds are unstable. It is therefore necessary to form solid dispersions of amorphous APIs in polymeric matrices to improve their stability.听Once an ASD reaches the intestine, the API is released in a supersaturated concentration. It has been reported that over 80% of ASDs offer improved bioavailability.

A key advantage of ASDs is the ability to provide the final drug product in the form of a tablet or capsule 鈥� the most common oral dosage forms. In addition, compared with lipid-based systems, ASDs allow the formulation of drug products with much higher dosage levels. Lipid-based formulations typically contain no more than 100 mg of API, whereas ASDs have much higher API-to-polymer ratios and loadings of as much as 300鈥�400 mg of active ingredient. Higher dosage formulations can benefit patients through reduced dosing frequencies and pill burdens.

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Two Leading ASD Technologies

Spray drying听(SD) and听hot-melt extrusion听(HME) are the two technologies most widely used for the preparation of ASDs. Both processes utilize a range of polymer excipients that have been approved for use in drug formulations.

The choice of听SD听or听HME听and the specific polymers used in a given ASD formulation depend on the properties of the API and the desired characteristics of the final drug product. Both technologies are effective for improving the bioavailability of poorly soluble drugs. However, temperature-sensitive APIs and APIs with high melting points are not suitable for听HME听processes. Solubility in appropriate organic solvents is a prerequisite for听spray drying.

HME听tends to be less expensive but generally requires the use of a large quantity of valuable API (up to 10 times that for听SD) to develop an optimal process. It is thus predominantly used for the development of generic formulations.听SD听is a simpler process and requires the use of less API (as little as a few hundred milligrams) during process development, so it is frequently used for the development of formulations based on novel APIs.

Maintaining the Metastable Form

Challenges in ASD process and product development relate largely to the fact that the amorphous API is a metastable form in a high-energy state. In nature, metastable forms undergo precipitation after a short period of time. It is therefore essential to stabilize the amorphous API so that precipitation does not occur during subsequent processing steps and shelf life.

During development of ASD drug product intermediates, 四色AV focuses on four primary aspects: performance in the GI tract, physical stability, chemical stability/compatibility between the ingredients and manufacturability. The key is selection of optimal formulation ingredients and conditions. For spray-dried ASDs, the solvent must be compatible with both the API and the polymer matrix. With all ASDs, the formulation must also be physically and chemically compatible.

It is also important to develop formulations that enable maintenance of the supersaturation window as long as possible once the API is released. The challenge is to identify the optimal API-to-polymer ratio (or API burden) that provides the best dissolution performance while maintaining the stability of the ASD intermediate and drug product.

There are also challenges associated with final drug production. It is important to ensure that the ingredients in the drug product do not promote precipitation of the API during tablet or capsule manufacture. As importantly, ASDs produced by听SD听and听HME听have properties, such as flowability, that are quite different from those of conventional (crystalline) powders used to manufacture tablets and capsules. The presence of high quantities of polymers with plastic/elastic properties creates the need for carefully designed process conditions that take into account dwell time and strain-rate dependencies. They also tend to be hygroscopic; equipment and processes must be designed and engineered to minimize exposure of the ASD intermediate and final drug product to moisture.

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Focus on Spray Drying

四色AV has been providing SD services听to the pharmaceutical industry for nearly 15 years. During that time, a significant amount of effort was undertaken to leverage all prior experience for each new听SD听project. Employing a听quality-by-design (QbD)听approach to understand the fundamentals of the听SD听process and build models for the prediction of spray-dried particle properties under various processing conditions is essential to process design and scale-up, and听QbD听adds predictability and significantly reduces risk in process development, scale-up and right-first-time clinical batch manufacturing.听The generated data resides in an extensive database and is used in combination with 四色AV鈥檚 proprietary modeling capabilities to closely correlate laboratory conditions to those at commercial scale in order to reduce the number of manufacturing runs needed to establish an effective commercial听SD听process.

Dealing with Brick Dust

As drug discovery efforts expand to more complex molecules, the percentage of candidates that are poorly soluble 鈥� but do not have properties that allow for ASD formation via SD or听HME听鈥� is increasing. These 鈥渂rick dust鈥� compounds have high melting points (> 200 掳C) and limited solubilities in volatile organic solvents. Non-ASD methods, such as nanomilling or complexation with cyclodextrin, are one option. Alternative ASD technologies, such as coprecipitation, are another.

One example of the latter is KinetiSol from DisperSol Technologies, which is based on a commercial plastic compounding process that was developed into a GMP pharmaceutical process by the company.听The solvent-free, fusion-based process requires high shear and is typically complete within 20 seconds at lab and commercial scale. Frictional and shear energies combined with high-intensity mixing lead to a rapid transition to the molten state.

Meanwhile, 四色AV has developed an advanced coprecipitation process using microfluidization that allows precise control of particle morphology and generates particles with surface areas that can be 10 times greater than those obtained using听HME听or听SD.听The API and polymer are dissolved in one solvent and mixed with an antisolvent (in which the ingredients are insoluble) under carefully controlled conditions in a microreactor. The generated API鈥損olymer coprecipitate consists of agglomerates of nanoparticles with unique physicochemical properties.

Facilitating ASD Development and Manufacturing

With nearly 15 years of commercial experience in the field of ASDs, 四色AV has been challenged to address a variety of problems in both formulation and process. In addition to听SD, we support projects involving ASD formation via听HME听and coprecipitation. We also provide complexation and nanomilling services if benchmarking studies indicate that they are the most appropriate technologies.

Our formulators and process development chemists/engineers have access to databases and modeling systems based on first principles that guide their efforts in formulation design and the identification of optimal conditions for ASD production. These tools allow 四色AV to avoid the unnecessary consumption of highly valuable API at the early project stages. As a result, we are able to develop optimal processes and formulations that provide the highest likelihood of success in terms of product and process performance.

In the area of contract manufacturing, 四色AV has been involved in the commercialization of approximately 90% of the current drug products that have been formulated as spray-dried ASDs. We bring this wealth of experience and knowledge to bear on each new project. We also accelerate projects by having all of our capabilities 鈥� API synthesis, ASD formulation and final drug product manufacturing 鈥� at one location. As a result of this vertical integration within the same site, projects can be implemented very rapidly, facilitating communication and interaction with customers and enabling product, process and analytical methods sharing. Clients report significant time-savings (by as much as 30%) when moving from API to tablets.

Greater Understanding for Rational Design

ASD has become a widely used technology platform that overcomes the challenges of slow dissolution and low bioavailability posed by poorly soluble APIs. Several products on the market were produced using听SD听and听HME, and it is expected that the number of drugs manufactured using a growing array of ASDs will continue to increase.

Greater understanding of the critical factors influencing ASD formation and performance gained through practical experience during product development and commercialization and intense academic investigation will only lead to further applications of ASD technology for the enhancement of solubility and bioavailability.

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