formulation design
HOW TO IMPROVE THE SOLUBILITY OF ACTIVE PHARMACEUTICAL INGREDIENTS ?
The causes of low solubility
High hydrophobicity and low water solubility are common characteristics of hits, leads, development candidates, and ultimately marketed therapeutic products. In spite of attempts to circumvent solubility problems in medicinal chemistry programs, approximately 70% of chemical entities currently under development have been suggested to be poorly water-soluble. The drivers of this solubility problem are clearly multivariate, and have been related to the implementation of high-throughput screening in discovery programs (which are often conducted in nonaqueous media), the search for enhanced receptor binding (which may be accomplished via promotion of hydrophobic interactions) and the identification of unprecedented targets that require lipophilic ligands for effective interaction. The problem of low water solubility has persisted over the years and continues to be a challenge to successful pharmaceutical development.
When does low solubility become a problem?
Although low water solubility presents varied and significant challenges throughout discovery and development, the greatest concern is generally the risk of reduced and variable absorption after oral administration. The value at which limited solubility begins to impact absorption is difficult to state definitively since it is dependent on a number of other system variables, including API permeability across the gastrointestinal (GI) epithelium, the target dose, and the pH and composition of the GI fluids. It is important to note that permeability and solubility are compensatory; that is, high permeability may offset low solubility in determining the maximum dose above which solubility in the GI tract becomes restrictive to absorption. By combining a compound’s GI solubility and permeability values in physiology-based pharmacokinetic (PBPK) models, it is possible to estimate the fraction of the dose that can maximally be absorbed. Knowledge of the maximum absorbable dose in turn is useful in determining which enabling formulation technology is required to overcome the solubility barrier.
High hydrophobicity and low water solubility are common characteristics of hits, leads, development candidates, and ultimately marketed therapeutic products. In spite of attempts to circumvent solubility problems in medicinal chemistry programs, approximately 70% of chemical entities currently under development have been suggested to be poorly water-soluble. The drivers of this solubility problem are clearly multivariate, and have been related to the implementation of high-throughput screening in discovery programs (which are often conducted in nonaqueous media), the search for enhanced receptor binding (which may be accomplished via promotion of hydrophobic interactions) and the identification of unprecedented targets that require lipophilic ligands for effective interaction. The problem of low water solubility has persisted over the years and continues to be a challenge to successful pharmaceutical development.
When does low solubility become a problem?
Although low water solubility presents varied and significant challenges throughout discovery and development, the greatest concern is generally the risk of reduced and variable absorption after oral administration. The value at which limited solubility begins to impact absorption is difficult to state definitively since it is dependent on a number of other system variables, including API permeability across the gastrointestinal (GI) epithelium, the target dose, and the pH and composition of the GI fluids. It is important to note that permeability and solubility are compensatory; that is, high permeability may offset low solubility in determining the maximum dose above which solubility in the GI tract becomes restrictive to absorption. By combining a compound’s GI solubility and permeability values in physiology-based pharmacokinetic (PBPK) models, it is possible to estimate the fraction of the dose that can maximally be absorbed. Knowledge of the maximum absorbable dose in turn is useful in determining which enabling formulation technology is required to overcome the solubility barrier.
Formulation strategies to address solubility problems
A wide variety of formulation approaches might be taken to address solubility challenges, including those that increase dissolution rate (e.g. particle size reduction techniques such micronization and nanonization), those that present the API in predissolved form to the gastrointestinal fluids (e.g. solubilized formulations based on cosolvents, surfactants and/or lipids) and those that modify the API’s crystal properties (e.g. salts, cocrystals, amorphous solid dispersions).
Which of these technologies is best suited to solve a given solubility problem depends on a multitude of factors. Enablement is usually one of the primary selection criteria (i.e. will the formulation deliver the right exposure benefit?), but considerations of stability, API payload in the formulation, tolerability, administration route and manufacturing complexity also drive technology selection. The relative weight of each of these factors in the decision-making process changes significantly as a compound progresses through development. For instance, liquid formulations are commonly utilized to permit administration of high doses in preclinical studies and to facilitate dose escalation in phase 1 clinical studies, but are typically replaced by more stable, higher-payload, solid dosage forms in later-phase clinical development.
Harpago’s unique approach to formulation design
Harpago specializes in the design and development of solubility-enhancing formulations for early-phase studies (discovery, preclinical, phase 1 and 2). We work closely with our customers to clearly understand the solubility problem at hand, and think to proactively to propose phase-appropriate formulation development options. Our formulation expertise includes those formulation technologies that have the most widely demonstrated industrial success, including nanosuspensions, amorphous solid dispersions and lipid-based formulations.
We differentiate ourselves from the competition through our in-depth understanding of oral biopharmaceutics, i.e. an understanding of how the dosage from will behave in vivo. We combine data obtained using biorelevant in vitro models and physiology-based pharmacokinetic (PBPK) models to make more informed formulation design decisions. Our focus on miniaturization further allows us to systematically generate high-quality data with minimum API consumption, which is especially useful for discovery-stage projects where API availability is almost invariably limited.
A wide variety of formulation approaches might be taken to address solubility challenges, including those that increase dissolution rate (e.g. particle size reduction techniques such micronization and nanonization), those that present the API in predissolved form to the gastrointestinal fluids (e.g. solubilized formulations based on cosolvents, surfactants and/or lipids) and those that modify the API’s crystal properties (e.g. salts, cocrystals, amorphous solid dispersions).
Which of these technologies is best suited to solve a given solubility problem depends on a multitude of factors. Enablement is usually one of the primary selection criteria (i.e. will the formulation deliver the right exposure benefit?), but considerations of stability, API payload in the formulation, tolerability, administration route and manufacturing complexity also drive technology selection. The relative weight of each of these factors in the decision-making process changes significantly as a compound progresses through development. For instance, liquid formulations are commonly utilized to permit administration of high doses in preclinical studies and to facilitate dose escalation in phase 1 clinical studies, but are typically replaced by more stable, higher-payload, solid dosage forms in later-phase clinical development.
Harpago’s unique approach to formulation design
Harpago specializes in the design and development of solubility-enhancing formulations for early-phase studies (discovery, preclinical, phase 1 and 2). We work closely with our customers to clearly understand the solubility problem at hand, and think to proactively to propose phase-appropriate formulation development options. Our formulation expertise includes those formulation technologies that have the most widely demonstrated industrial success, including nanosuspensions, amorphous solid dispersions and lipid-based formulations.
We differentiate ourselves from the competition through our in-depth understanding of oral biopharmaceutics, i.e. an understanding of how the dosage from will behave in vivo. We combine data obtained using biorelevant in vitro models and physiology-based pharmacokinetic (PBPK) models to make more informed formulation design decisions. Our focus on miniaturization further allows us to systematically generate high-quality data with minimum API consumption, which is especially useful for discovery-stage projects where API availability is almost invariably limited.
Discuss your solubility problem
If you would like to learn more about our approach to tackle solubility problems, you can reach out to one of our experts here. We are happy to make an assessment of the developability of your compound and to propose a suitable formulation development trajectory.
