Merck

Solid Formulation Strategies

Many tablets of different shapes and colors

Solid formulation is well-established in the pharmaceutical industry and there are many standard processes and methods, as well as a variety of formulations and dosage types. Challenges such as poor solubility remain, however, and necessitate innovative problem-solving strategies.

This page provides an overview of common challenges in solid formulation of small molecules, highlighting effective and tailor-made solutions specifically developed to overcome critical obstacles in drug development.


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Tablet with enhanced API solubility

Enhancing API solubility

Solubility enhancement is a key challenge in pharmaceutical formulation development, as an increasing number of APIs in the development pipeline are poorly water-soluble. A range of approaches are available to enhance solubility which have to be evaluated depending on the API and specific formulation requirements as there is no one-size-fits-all solution for poorly water-soluble APIs. Strategies for solubility enhancement are typically based on the classification of the API according to the Biopharmaceutics Classification System (BCS), or the more recent Developability Classification System (DCS), resulting in a tailored approach for the individual API.

  • The physicochemical properties of solid form APIs can be modified and enhanced using different API processing methods including salt formation, co-crystals, and nano-milling. These approaches can enhance many API properties including solubility, processability, physical and chemical stability, and safety.
  • Oral formulations require API solubility for sufficient absorption in the body. If the API is not appropriately dissolved in the gastrointestinal tract, it cannot enter the systemic circulation and the intended physiological effect will not be realized. A variety of approaches can be used for solubility enhancement through formulation including different solid dispersion technologies.

    • In hot melt extrusion (HME), a solid dispersion of the API in a polymeric drug carrier is formed through mixing and melting inside the heated extruder barrel.
    • Inorganic drug carriers such as mesoporous silica can be used to form a solid dispersion by adsorbing the API, typically in its better soluble amorphous state.
    • Spray drying creates a solid dispersion through rapid solvent evaporation of an API solution.
    • Dissolution enhancers can be used to improve performance of dissolution-rate limited APIs.
    • Replacing hydrophobic excipients with hydrophilic excipients is another approach to improve solubility and dissolution performance of a formulation.
    • In addition to its application as a counter ion in salts, meglumine can also be used as a functional excipient to enhance API solubility, improve API stability, and adjust pH value.
    Tablet being 3D printed

    Pharmaceutical development and manufacturing is moving away from the concept of “blockbuster drugs” and toward addressing the needs of very defined patient populations. At the same time, process efficiency and process economics are now more important than ever. New technologies are on the rise and offer new opportunities and the potential to disrupt traditional pharmaceutical manufacturing concepts.

    • 3D printing is an attractive technology that enables personalization and on-demand manufacture, flexibility in release performance and final dosage form, digitalization, and automated formulation.
    • Characteristics of the API can have an impact on the performance of the manufacturing process and final formulation. Particle homogenization platform technologies can be used to address unstable polymorphs, and improve API flowability, compressibility, and particle homogeneity to enable reliable formulation and more efficient tableting processes.
    • While traditional batch manufacturing is very established in the pharmaceutical industry, it has several drawbacks which result in a limited process efficiency. In times where speed and process economics are key, continuous manufacturing can be a more efficient approach to solid dose manufacturing.
      Tablet coating

      Tablet coatings play an important role in solid dose formulation as they offer numerous benefits. They improve appearance, mask unpleasant colors or tastes, differentiate from other drug products, protect the tablet core from moisture, modify the release behavior, and improve swallowability. The development of a coating formulation and a process to ensure optimal performance requires substantial expertise. Also, the selection of the coating components is a critical step and material-specific properties have to be taken into consideration, as well as recent regulatory developments.

      • Coating the dosage form is a highly efficient approach for protecting the API from environmental effects and improving its appearance at the same time. Selecting a coating polymer with good oxygen and moisture barrier properties is important for a good protective effect.
      • Titanium dioxide (TiO2) is widely used as a colorant in tablet coatings and a uniform white appearance across batches improves aesthetics and patient compliance. However, titanium dioxide is no longer considered safe for use in foods and dietary supplements in the EU and its removal from pharmaceutical products is now being considered. Viable alternatives to titanium dioxide are available for use in film coatings helping to mitigate regulatory risks in the future.
        Tablets in rows

        Despite being one of the most widely used oral solid dosage forms, formulation of compressed tablets can be challenging, and several manufacturing approaches can be used. Formulators benefit from greater flexibility when selecting the best technology during formulation development for their specific API and final formulation requirements. Learn about the common techniques for tablet manufacturing direct compression, wet granulation, and dry granulation, and their respective benefits and drawbacks.

        • The advantageous physicochemical characteristics of particle-engineered mannitol filler excipients enable broad flexibility in manufacturing processes, even for more challenging solid dose formulations such as low and high dose and micronized APIs. 
        • Tableting performance in dry granulation processes is strongly dependent on the excipient type used. A number of commercially available mannitol options are suitable for dry granulation, including spray-dried, granulated, and crystalline mannitol grades. Explore the range of mannitol types and case studies describing how they differ. 
        • Direct compression is a time-saving process with fewer steps compared to wet granulation and is also well suited for sensitive APIs. Use of functional excipients helps to overcome potential limitations of direct compression associated with particle size differences and high/low dose levels, which could otherwise result in de-mixing and impact content uniformity.
          API stability

          Many factors in a drug formulation can have a negative effect on the stability of the API. Reduced API stability can result in reduced shelf life, reduced efficacy, or in the worst-case scenario, cause harm to a patient. There are several considerations that must be taken into account when developing a formulation or when dealing with instabilities: Is the API sensitive to environmental factors such as light, heat, or humidity? Is the API prone to instabilities induced by common excipient impurities such as peroxides or reducing sugars? Is the API incompatible with selected formulation methods?

          • Use of the right excipients for tablet cores, capsules, and sachets can help protect APIs from browning due to reducing sugars and peroxide impurities, heat- or moisture-induced instabilities during the granulation process, and instabilities promoted by hygroscopic formulation components.
            Administration of tablet to child

            Pleasant taste and palatability influence patient acceptance of a final formulation and can have a significant impact on patient compliance. These factors are particularly relevant for oral administration routes, liquid formulations, orally disintegrating tablets (ODTs), and certain patient groups (pediatric, geriatric).

            • Taste enhancement using flavorings and sweeteners is broadly applied and well-accepted. Taste masking includes complex formulation approaches such as particle coating, inclusion complexation, or microencapsulation. When choosing a synthetic or natural sweetener, safety and carcinogenicity must be considered. High-intensity sweeteners, such as sucralose and neotame, provide a simple and effective solution as they feature high sweetness factors, mask bitterness with ease, and are non-carcinogenic and safe. 
              Clock and tablet which is releasing API

              Controlled release of oral solid formulations ensures alignment of drug performance and therapeutic need. The benefits of sustained release include reduced dose frequency, greater patient convenience, and increased compliance. In many cases, long-acting efficacy of the API is required. When selecting excipients for sustained-release formulations, drug manufacturers require options that deliver superior reliability and consistency with release kinetics unaffected by outer conditions such as pH value.

              • Matrix systems are widely used to control drug release due to their simple formulation process. In contrast to rate-controlling coating layers, a matrix formulation generally has a reduced risk of dose dumping and related side effects. A new functional excipient based on polyvinyl alcohol (PVA) with optimized particle size and properties provides consistent, sustained drug delivery over long periods and is well suited for direct compression processes due to its good compressibility. The fully synthetic nature allows for tight control of properties and reliable batch-to-batch performance, supporting Quality by Design (QbD) approaches. 
                Tablet disintegrating

                Orally disintegrating tablets (ODT) offer convenience and speed. These tablets are designed to dissolve quickly in the mouth before being swallowed, without the need for water.

                • The selection of excipients tailored for ODTs is critical to ensure robust tablets can be produced at low compression forces as well as rapid disintegration and dissolution. 
                  Two inhalers

                  Inhalation drug delivery is an attractive, noninvasive route of administration when rapid onset of action, minimal side effects and excellent bioavailability are desired. Accurate dosing of the dry powder inhalation (DPI) formulation can be challenging, however, due to the small amount of dosage and fine particle size required.

                  • Combination with solid excipient carriers is often necessary to improve drug stability, dose control, and prevent particle cohesion. Currently, most powder blends for DPI formulations are based on lactose monohydrate as an excipient carrier which can result in possible interaction of the lactose (being a reducing sugar) with the API, concerns for lactose intolerance in patients, and the use of an excipient of animal origin. Mannitol-based excipients may help to overcome the shortcomings of lactose-based inhalative formulations.

                    Formulating solid dosage forms can be quite challenging and complex. On the way to the final formulation, there are many obstacles to overcome, whether it is API stability, bioavailability, or release kinetics that have to be optimized, just to name a few. Finding a trusted partner with application and regulatory expertise that supports you in identifying the best approach for your specific API can make a difference – helping you to reduce efforts, accelerate development time, and ultimately, bring your drug development project to success.

                    Contact our technical experts to learn more about our extensive application services.


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