API Solubility and Dissolution Enhancement Via Formulation

• API Solubility and Dissolution for Solid Formulations
• The Developability Classification System
• Formulation Approaches
• Formulation Approaches for Dissolution-rate Limited (DCS IIa) APIs
• Formulation Approaches for Solubility Limited (DCS IIb) APIs
• Choosing Which Option for API Solubility Enhancement

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.

API Solubility and Dissolution for Solid Formulations

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 Developability Classification System Aids in Formulation Development of Poorly Soluble APIs

The Biopharmaceutical Classification System

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.

• BCS Class I, which includes APIs that are highly soluble and highly permeable
• BCS Class II, which includes APIs that have low solubility and high permeability
• BCS Class III, which includes APIs that have high solubility but low permeability
• BCS Class IV, which includes APIs that have low solubility and low permeability

Figure 1. The Biopharmaceutical Classification System classifies APIs in terms of permeability and solubility into four classes of APIs.

The Developability Classification System

The BCS served as a basis for the Developability Classification System (DCS) (learn more about the DCS in our whitepaper).

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:

• Dissolution rate-limited: The dissolution rate is too slow for the API to dissolve during the time of passage by the site of absorption (usually the small intestine).
• Solubility-limited: The solubility is too low for the required amount of API to dissolve in the available GI fluid volume.
• Permeability-limited: The rate of transfer from the GI tract through the intestinal membrane is too low. There is limited influence on permeability by the excipient's choice and formulation.

Both solubility and dissolution rate can be optimized either during API processing or during formulation development:

• During API processing:
  o   Improve API dissolution by reducing the particle size.
  o   Improve API solubility by altering the API’s chemical nature.
• During formulation development:
  o   Improve API dissolution by accelerating the disintegration.
  o   Improve API solubility by using physical approaches or using solid dispersion techniques.

The DCS Guides Formulation Approaches

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.

Formulation Approaches for Dissolution Rate-limited (DCS IIa) APIs

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.

Accelerating Disintegration of APIs

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).

Enhancing Dissolution of APIs

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

Replace Hydrophobic Lubricants with Hydrophilic Lubricants During Formulation

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.

Table 1. Comparison of available methods for dissolution rate-limited APIs, including criteria to support the method selection process as well as method-specific benefits and drawbacks

Dissolution Rate ltd	Disintegration Acceleration	Dissolution Enhancers	Hydrophilic Lubricants
Short description	Speed up tablet disintegration, e.g. by adding a super-disintegrant to tableting mixture	Speed up dissolution, e.g. by using surfactants that promote the contact of API and outer medium and accelerate diffusion rate	Improve hydrophilicity, disintegration, and dissolution behavior by replacing hydrophobic with hydrophilic lubricants
Decision basis	API dissolution rate: low Tablet disintegration: slow	API dissolution rate: low Wettability: low	API dissolution rate: low Process requires lubrication: yes Disintegration challenges with hydrophobic lubricants: yes
Pros	Easy application: addition of excipient to tableting blend CM suitable Standard tableting equipment is feasible Broadly used in solid dose formulation	Easy application: addition of excipient to tableting blend CM suitable Standard tableting equipment is feasible	Easy application: addition of excipient to tableting blend CM suitable Standard tableting equipment is feasible No retarding effect* No overlubrication*
Cons	Potential incompatibilities of tablet ingredients	No specific disadvantages	Lubrication effect typically lower*, no glidant/anti-adherent effect*   *In comparison to hydrophobic lubricants

Formulation Approaches for Solubility-Limited (DCS IIb) APIs

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.

Hot Melt Extrusion

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.

Inorganic Drug Carriers

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

Table 2. Comparison of described methods for solubility limited APIs, including criteria to support the method selection process as well as method-specific benefits and drawbacks

Solubility ltd	Hot melt extrusion	Drug carriers	Spray drying
Short description	Dispersion of the API within a polymeric carrier through heating and mixing	Adsorption of the API on large surface area of an inorganic carrier	Dispersion of the API within a polymeric carrier through atomizing and subsequent drying of an organic API-polymer solution
Decision basis	API aqueous solubility: low Thermostable API: yes* Melting point: low (high can also be possible)	API aqueous solubility: low API solubility in organic solvent (low boiling point, high vapor pressure): good Thermo-labile API: yes Poor glass former: yes / stable in amorphous form: no	API aqueous solubility: low API solubility in organic solvent: good Thermo-labile API: yes
Pros	CM (Continuous manufacturing) suitable Solvent-free High flexibility and versatile downstream options (e.g. final dosage form; release profile) Addition of plasticizers extends application range Good scalability	CM suitable Suitable for thermosensitive APIs/APIs with a high Tm Only solvent suitable for API needed (not common solvent for both API + carrier) Stabilizing effect on poor glass formers (storage stability) Low investment (standard equipment) Different loading techniques applicable	CM suitable Broadly applied, also in production scale Low thermal impact Fast process with a high throughput Versatile process possibilities: use of various polymers and APIs, amorphous solid dispersion generation or encapsulation Dedicated particle design Good scalability
Cons	HME is typically not suitable for temperature-sensitive APIs* Potential storage stability issues (recrystallization tendency of poor glass formers) Potential interactions of polymer & API *for Parteck® MXP excipient specifically, the processing temperature range is very broad and extends to APIs with low and high melting points	Organic solvents Not suitable for high API doses (limited by tablet size and max. amount of loaded carrier per tablet) High operating costs Residual solvent risk	Organic solvents (common solvent for API and polymer required) Risk of in-process recrystallization (due to rapid drying of droplets) and potential storage stability issues (recrystallization tendency of poor glass formers) Physicochemical properties of spray-dried solid dispersion typically not suited for DC (e.g. poor flowability) High equipment footprint and operating costs Residual solvent risk

To learn more about our functional Parteck^® excipients, click on the link below.

Choosing Which Option for API Solubility Enhancement During Formulation

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:

1. To begin, determine the solubility in fasted state simulated intestinal fluid (FaSSIF) and consider what volume is required to dissolve the maximum dose.
2. Determine the permeability either (a) experimentally using a permeability assay that measures the rate of flux of compound permeating across a Caco-2 cell monolayer or (b) theoretically using computational simulation.
3. If the volume required to dissolve the maximum dose is below 500 mL, then your drug is considered highly soluble.

• If your drug is highly soluble and has a permeability of >1 cm/s x 10^-4, then your drug belongs in DCS Class I. You do not need any further steps to improve solubility or permeability.
• If your drug is highly soluble and has a permeability of <1 cm/s x 10^-4, then your drug belongs in DCS Class III. Permeability is difficult to address during formulation, but options include lipid-based drug delivery systems, self-emulsifying systems, or prolonging the GI tract residence time. However, for APIs with low permeability, the prediction of effects is not as easy as for dissolution/solubility-limited APIs as transporter/efflux effects can also play a role.

4. If the volume required to dissolve the maximum dose is greater than 500 mL, then your drug has low solubility, and you’ll need to take steps to improve solubility.

• First consider permeability. If your drug has a permeability of <1 cm/s x 10^-4, then your drug belongs in DCS Class IV. There are methods you can take such as API processing or lipid-based formulation techniques, but success rates might be lower as these compounds are more challenging.
• If your drug has a permeability of >1 cm/s x 10^-4, then your drug belongs in either DCS Class IIa or DCS Class IIb and there are many options to take from here.
  • If your drug’s dose:solubility ratio and permeability combination put it above the SLAD line, then your drug is in DCS Class IIa and you can consider methods to enhance dissolution performance such as using our Parteck^® PLX 188 or Meglumine excipient to speed up the dissolution rate.
  • Drugs that are below the SLAD line are considered DCS Class IIb and you have several options to improve solubility:
• If the melting point is <250 °C you can use hot melt extrusion with PVA-based Parteck^® MXP excipient. However, if the API shows stability issues when in its amorphous form, using an inorganic drug carrier like Parteck^® SLC excipient could be a better suited alternative.
• If the melting point is >250 °C and the API is soluble in organic solvents, you can use an inorganic drug carrier, such as the Parteck^® SLC excipient.

Overview: How to Apply DCS in Formulation Development

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.