In the development of New Chemical Entities (NCEs), their low aqueous solubility will drastically affect their bioavailability. Understanding at an early stage the behavior and characteristics of these APIs is required to ensure the development of drug products with adequate performance.
This article presents the different strategies considered to enhance drug bioavailability with a special focus on solubility improvement through amorphous solid dispersion.
Introduction: The Benefits of Pre formulation to Predict Bioavailability
To optimize drug performance through the development of an efficient dosage form, the characterization of the physicochemical properties of New Chemical Entities (NCE) needs to be carried out. These studies are defined as pre-formulation studies. A thorough understanding of these properties may ultimately provide a rationale for formulation design or support the need for molecular modification. Among these pre-formulation studies, the characterization of solubility and gastrointestinal permeability of the API is critical. Indeed, according to the Biopharmaceutics Classification System (BCS) and the corresponding FDA guidance, drug substances are categorized into four groups, based on their aqueous solubility and gastro-intestinal membrane permeability.1 The combination of these two factors will determine oral drug absorption.
Nowadays, BCS class II drug substances (with low solubility and high permeability) are the most common category for NCEs. Approximately 75% of NCEs under development are poorly soluble in water which results in various formulation-related performance challenges.2
Indeed, for orally administered drugs to be absorbed into the systemic circulation, their solubility plays a vital role in this process, as only the dissolved fraction of the API can cross the intestinal membranes.
Drug developers use many technologies to address bioavailability challenges, but taking a sequential approach to technology selection can be time-consuming and costly. A better approach is to select the optimal technology based on a compound’s physical, chemical, and biological properties through pre-formulation studies.
Below, the scheme highlights the key properties that need to be measured in order to determine the appropriate formulation solution.
As part of the critical parameters of the targeted compound, solubility is a function not only of chemical structure but also of solid state, through its crystal form.
Thus, identifying the cause of the poor gastro-intestinal solubility of an API is key to rationalizing the formulation development. Indeed, low gastrointestinal absorption of NCEs can be driven by slow dissolution kinetics or can be truly solubility-limited due to either crystal energy (e.g. high crystal forces in the molecular assembly can inhibit dissolution) or the lipophilicity of the molecule. These types of compounds are often referred to as:
- “grease ball” compounds: high LogP (often over 4) which translate into low water solubility and high solubility in lipophilic environments.
- “brick dust” compounds: very stable crystalline structure with high melting points (often over 200°C). Brick dust compounds are often not particularly lipophilic, they neither dissolve easily in oils nor water.
Therefore, to address the poor drug solubility challenge, depending on the properties of the drug molecules, different formulation strategies will be required to increase their dissolution rate, solubility, and ultimately bioavailability.
Solutions to Improve Solubility and Bioavailability of the Drug
Numerous technologies are available to address solubility challenges. Modifications of the solid state of API, like drug particle size reduction, polymorphism (e.g. phase transition, solvates/hydrates), or amorphization are methods that need to be considered during drug development for poorly soluble drugs. Salt formation is also a common and effective approach for increasing the solubility and dissolution rates of acidic and basic drugs.
Other techniques based on carrier or delivery system can also be used, like for instance, complexation using cyclodextrins to increase apparent solubility, lipid-based formulation (LBF) delivery, or amorphous solid dispersions (ASD) to increase both dissolution rate and solubility.4
The choice of the technique depends on the specific properties of the active ingredient, the desired dosage form, and the target therapeutic application. At commercial scale, amorphous solid dispersion (ASD) is one of the most frequently used technologies to improve bioavailability.5
ASD is a solid dispersion in which the active ingredient is dispersed within an excipient matrix (typically polymers) in a substantially amorphous form. The amorphous state of the drug in ASDs is critical for increasing its solubility. With the drug in an amorphous form, no energy is required to break the drug crystal lattice. For this reason, compared to the crystalline form, the amorphous form of many poorly water-soluble drugs can achieve substantially higher apparent solubility with faster dissolution. At large scale, an ideal manufacturing process should be able to produce homogenous ASDs that can retain their amorphous form long enough to support the life cycle of the drug.
ASDs may also have a higher wettability due to the presence of hydrophilic polymers. Based on formulation composition, solid dispersions are classified as first, second, or third generation.
- Solid dispersions prepared using crystalline carriers are the first generation. Their drug release rate is generally slower than the other two generations of solid dispersions.
- ASDs, which consist of an amorphous drug in combination with an amorphous polymer, constitute the second generation.
- ASD formulations could also contain additional excipients, such as polymer and/or surfactants and plasticizers to further enhance drug release and stability. Such ASDs are known as the third generation.
The liquid/amorphous form of a drug has higher free energy than the crystalline form, hence a tendency for crystallization. “Brick dust molecules” are drugs with very low aqueous solubility and are difficult to formulate for instance as lipid-based formulations (LBF) as they also exhibit poor lipophilic solubility. Because a high melting point might be derived from high crystallinity and high intermolecular forces in the solid state, disruption of these intermolecular forces is considered a method to overcome the poor solubility and enhance the water solubility of API candidates.
Case Study With a Brick-Dust Molecule to Improve Its Bioavailability
The API of interest is a weak base classified as a class II API in the Biopharmaceutics Classification System (BCS): low solubility mainly at pH above 3.9 and high permeability.
Pre-Formulation Studies
The measurement of the compound melting point and LogP classified the API as a “brick dust” (melting point >200 °C, cLog P<2), with poor solubility in both aqueous and lipophilic solvents due to its strong crystalline lattice. Furthermore, the corresponding crystalline form showed a pH-dependent solubility (Figure 1). When increasing the pH of the dissolution medium from 1.2 to 7.4, the solution precipitated at pH 7.4, when in its neutral form, reaching 15% of dissolution after 30 min at pH 7.4.
Knowing that the studied API is a “brick dust”, the choice of an ASD technique for improving its solubility and bioavailability, maybe the most promising solution. Thus, an ASD formulation of the API by Hot-Melt Extrusion (HME) was developed and characterized, following a polymer screening. A polymer of interest was selected thanks to its high thermal stability and its ability to reduce the API product’s melting point, indicating its ability to dissolve in the polymer matrix. Another compound was also added as a plasticizer. Next, the product formulation by ASD (API-ASD) was produced and characterized.
A solid-state characterization confirmed the conversion of the drug to its amorphous form within the dispersion. The extrudates (API-ASD) were still amorphous after three weeks at ambient conditions.
The ASD formulation of the targeted API product exhibited enhanced dissolution at pH 7.4, reaching a plateau of around 37% dissolution after 30 minutes, whereas the crystalline form barely reached 1% (Figure 3). In this case, the ASD formulation increased the product’s solubility of the neutral form by almost 40-fold. When simulating intestinal conditions with Fasted State Simulated Intestinal Fluid (FaSSIF) medium, the API-ASD (API-formulated by ASD) showed an enhanced dissolution by more than 6-fold, reaching 85% in less than 30 min vs 13% for the API. The ASD did not precipitate when reaching pH 7.4, whereas the corresponding crystalline form slowly precipitated to reach 6% dissolution at the end of the experiment. Hence, in intestinal conditions, the ASD formulation was superior to the crystalline form of the API.
Conclusion
Following pre-formulation and early-formulation studies, the API was classified as a brick dust and its formulation by amorphous solid dispersion (ASD) would likely improve its oral bioavailability. Indeed, the API formulated by ASD showed clear enhanced dissolution properties over its crystalline form in intestinal conditions, allowing for potentially better drug absorption and systemic exposure. The production of API formulated by ASD, more especially by Hot-Melt Extrusion (HME) could therefore be a promising technique for the development of a new improved formulation with increased bioavailability. Most importantly, when selecting the right technology for drug formulation to provide stabilized APIs and increased solubilization, the following factors need to be considered:
- properties of the API,
- intended final dosage form,
- cost of scale-up,
- IP Protection.
Understanding the behavior and the performance of the API properties at an early stage is a key requirement for reaching a successful formulation solution. Pre-formulation studies, including physicochemical characterization, excipient interaction, solubility, and biorelevant dissolution studies are the essential foundations for selecting and rationalizing formulation techniques.
A successful development of amorphous solid dispersion formulations depends on three primary factors: active pharmaceutical ingredient properties, stabilizing polymer, and processing technology.
References
- Amidon KS, Langguth P, Lennernas H, Yu L, Amidon GL. Bioequivalence of oral products and the Biopharmaceutics Classification System: science, regulation, and public policy. Clin. Pharmacol. Ther. 2011; 90:467–470.
- J Han J, Wei Y, et al. Co-amorphous systems for the delivery of poorly water-soluble drugs: Recent advances and an update, Expert Opinion on Drug Delivery (2020), DOI: 10.1080/17425247.2020.1796631.
- Bednarek R. In Vitro Methods for Measuring the Permeability of Cell Monolayers. Methods Protoc. 2022 Feb 9;5(1):17. doi: 10.3390/mps5010017.
- Vasconcelos T, Marques S, das Neves J, Sarmento B. Amorphous solid dispersions: Rational selection of a manufacturing process.Adv Drug Deliv Rev. 2016 May 1;100:85-101.
- Iyer, Raman, et. al. Amorphous Solid Dispersions (ASDs): The Influence of Material Properties, Manufacturing Processes and Analytical Technologies in Drug Product Development. Pharmaceutics, 2021, 13(10), 1682.https://doi.org/10.3390/pharmaceutics13101682.
Author Details
Sonia Lombardo- Preformulation Engineer Solid State; Lucile Rametti- Innovation Project Manager; Julien Leroudier- Head of Solid State; Hong Shen-Analytical Services Director; Juliette Martin- Scientific Communication Manager; Julien Boutet- Head of Innovation; Gautier Decock- CRDO & Early Phase Director; SEQENS
Publication Details
This article appeared in American Pharmaceutical Review: Vol. 27, No. 3April 2024Pages: 48-52
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