A common challenge of using high-throughput screening and target-oriented drug discovery is poor API solubility. More and more APIs in development are challenging with estimates between 70-90% are poorly soluble.
Any oral formulation requires good API solubility for sufficient absorption in the body. If the API is not fully or just partly dissolved in the gastrointestinal (GI) fluids at the site of absorption, it cannot pass the gastrointestinal membrane and enter the systemic circulation. Thus, the intended physiological effect will not be realized.
For solid formulations, both solubility and the dissolution rate are critical factors for bioavailability and a therapeutic effect. While solubility addresses the extent to which an API can dissolve in a solvent, the dissolution rate is the rate at which the API dissolves in liquid. Both factors affect how much of the API dissolves in a limited amount of gastrointestinal fluid and how quickly it dissolves. This is why both have an immediate effect on the extent of absorption and, as a result, bioavailability.
The Biopharmaceutical Classification System (BCS) was developed in the 1990s and is still used by the FDA for biowaivers. It provides a framework that considers factors such as solubility and permeability that affect API in vivo performance.
As shown in Figure 1, there are four classes of APIs based on solubility and permeability in the BCS system.
Figure 1.The Biopharmaceutical Classification System classifies APIs in terms of permeability and solubility into four classes of APIs.
The DCS adds the solubility-limited absorbable dose (SLAD) line to further differentiate APIs within Class II (Figure 2). The SLAD line indicates that drugs above the line are dissolution rate limited (DCS Class IIa) and drugs below the line are solubility limited (DCS Class IIb). For the final drug to succeed, especially in terms of therapeutic efficacy, it’s critical to address both solubility and the dissolution rate.
Figure 2.The Developability Classification System for APIs adds to the Biopharmaceutical Classification System by including Class IIa for dissolution rate limited APIs and Class IIb for solubility limited APIs.
The DCS aims to support formulators by categorizing APIs based on what is limiting their absorption: dissolution rate, solubility, or permeability:
Both solubility and dissolution rate can be optimized either during API processing or during formulation development:
The DCS guides the selection of the most suitable approach for formulation to enhance solubility. These approaches are categorized into methods to address dissolution rate limited APIs (DCS IIa) and those that address solubility limited APIs (DCS IIb) (Figure 3).
Figure 3.Different options are available to enhance API solubility depending on whether the API is limited by the dissolution rate (DCS IIa) or by solubility (DCS IIb). Both limitations can be addressed by API processing or by enabling formulations.
DCS Class IIa APIs are limited by their dissolution rate which is why they can benefit most from formulation approaches that speed up dissolution to increase absorption and improve the therapeutic effect. While there are steps you can take to improve the dissolution rate during API processing to reduce particle size (ex: micronization or nano-milling), this article will focus on formulation approaches.
To accelerate disintegration, you can use Parteck® M or superdisintegrants (e.g. Parteck® CCS croscarmellose) during API formulation to promote the rapid breakdown of a tablet into its primary particles. These superdisintegrants are super-absorbing materials that swell upon contact with saliva or gastrointestinal fluids.
In addition to superdisintegrants, another option to speed up disintegration would be to create a porous tablet via lyophilization, to use hydrophilic pore formers, or to add an acid and carbon dioxide source (ex: effervescent tablets).
Another way to increase the API’s dissolution rate is to use amphiphilic polymers such as surfactants (Figure 4) to enhance the wetting of the API within the gastrointestinal tract, improve dispersibility, bring the API into solution, and keep it in solution. When the API is in the solution, it can be absorbed. Poloxamers, a co-polymer of poly(ethylene oxide) and poly(propylene oxide, (e.g. Parteck® PLX 188 poloxamer) are excipients widely used in the pharmaceutical industry to enhance dissolution rate. The excipients are safe in a variety of different dosage forms and are compatible with a wide range of APIs. Additionally, meglumine can also be used as a dissolution enhancer.
Figure 4.Working principle of an amphiphilic polymer when applied to improve dissolution performance of a DCS Class IIa API
Hydrophobic lubricants (e.g. magnesium stearate, calcium stearate, stearic acid, or glyceryl di-behenate) are used in many pharmaceutical processes due to their lubrication efficacy. This quality prevents tablets from sticking to equipment and reduces ejection force. However, hydrophobic lubricants can reduce tablet disintegration and dissolution rate. Replacing a hydrophobic lubricant with a hydrophilic lubricant (e.g. Parteck® PLX 188 excipient) during formulation avoids this effect.
Addressing solubility limited APIs during formulation uses solid dispersion technologies while addressing solubility during API processing using techniques such as salt or cocrystal formation, polymorph screening, or prodrug formation. Here, we’ll cover formulation approaches.
With hot melt extrusion (HME), the API is heated and mixed with a matrix polymer (ex: Parteck® MXP polyvinyl alcohol) (Figure 5). The mixture is then extruded to provide a homogeneous dispersion of the API within the polymer on the molecular level, converting a poorly soluble drug from its crystalline form into a stabilized amorphous form. As a result, this creates an amorphous solid dispersion with an increased dissolution rate. HME is compatible with direct compression and continuous manufacturing. As an alternative to HME, Parteck® MXP can also be used to form a solid dispersion via 3D printing.
Figure 5.The API is mixed with a matrix polymer in the extruder to enable homogeneous dispersion of the API within the polymer.
Silica is commonly used in solid-dose manufacturing. For solubility enhancement, not just any silica can be used. For example, the Parteck® SLC mesoporous silica is specially designed with a high surface area and mesopores with a specific diameter. Through nanoconfinement in its porous structure, it stabilizes APIs in their better soluble, amorphous form, even at high drug loads. The absorption on its surface area significantly reduces molecular mobility and prevents recrystallization – which makes it a suitable approach even for compounds like poor glass formers that face recrystallization challenges when using other approaches (e.g. often encountered in HME formulations during storage). Case studies show that Parteck® SLC mesoporous silica can be applied for a broad range of APIs using commonly available lab equipment and can therefore serve as a platform technology in formulation development.
For this application, the API needs to be loaded onto the surface of the silica particles, such as by dissolving the API in organic solvent and removing the solvent during the loading process (Figure 6).
Figure 6.Mode of action for inorganic drug carriers
To learn more about our functional Parteck® excipients, click on the link below.
While there are many options available for enhancing the formulation to improve API solubility and dissolution, a formulation approach that works for one API might not be suitable for another API. Thus, it’s increasingly important to be able to choose from several available solutions at hand as each has unique benefits. To determine the best method, take into account API properties such as solubility, permeability, melting point, solubility in organic solvents, and stability of the amorphous form.
Our decision tree below can help you decide which approach to take:
Decision tree that illustrates how a formulator can identify the best approach for the respective API Alt text: Flow chart of formulation approaches to improve API solubility and dissolution.
Depending on the individual needs (which are determined by the API properties and desired final formulation performance), there are different options available to choose from to improve API solubility and dissolution. It is extremely important to pinpoint the exact reason behind a solubility issue and select a targeted formulation approach. As the root cause is typically API dependent, a formulation approach that works for one API might not be suitable for another API. As such, it is increasingly important for formulators to be able to choose from a number of available solutions at hand.
To continue reading please sign in or create an account.Don't Have An Account?