Solubility Solutions: Formulators Have a Growing Toolbox to Increase Uptake of OSDs

When addressing solubility challenges, one size doesn’t fit all. Sixty to seventy percent of compounds in development are poorly water soluble (BCS II & IV) and as high as ninety percent for certain drug categories.1 

Approaches to improve solubility and bioavailability of poorly soluble APIs include particle size reduction, complexation systems, lipid-based systems, and polymers & solid dispersions. Each approach has disadvantages, no one technology works on all components, and the number of poorly soluble compounds is increasing. Below is a discussion on the utility of diff erent strategies. 

Particle Size Reduction 

Particle size reduction increases the specific surface area of API particles, enabling significant improvements in dissolution rate, and thus, bioavailability. Conventional processes such as milling, high-pressure homogenization, and spray drying are well-established and widely used for particle size reduction. However, adverse results that can occur during processing— including a broader particle size distribution (PSD), thermal, and chemical degradation of the product—are major concerns for the product quality.² 

Complexation Systems 

Complexation techniques can improve the solubility of poorly water-soluble drugs. The cyclodextrin (CD) complexation and phospholipid (PL) complexation are among the more popular investigated methods employed for more precise improvement of the solubility and dissolution of poorly water-soluble drugs.³ The cylindrical shape of CD allows the guest API to be kept within the hydrophobic interior, while the exterior of the CD is hydrophilic and soluble in an aqueous solution. This complex improves the drug solubility and ultimately the bioavailability of insoluble drugs. The challenge with complexation systems is the need for a relatively high mass fraction of, e.g., cyclodextrin compared to the drug mass fraction, which limits the total amount of API in the system. Additionally, the weak binding and dissociation of complexes upon dilution in the complexation systems can pose some limitations. In some cases, drug complexes are unable to permeate the lipophilic epithelium membranes, which may result in low bioavailability, especially for BCS class III drugs.

Lipid-based Systems 

Lipid-based drug delivery systems (LBDDS) are a wide-ranging designation for formulations containing dissolved or suspended drugs in lipidic excipients. Lipids are esters of fatty acids – lipophilic hydrocarbon chains linked to hydrophilic groups like glycerol, polyglycerol, or polyalcohol.⁴ LBDDS can be as simple as a drug mixed with oil to a more complex formulation that is designed to spontaneously emulsify upon contact with aqueous media. Such formulations are self-emulsifying drug delivery systems (SEDDS) or self-micro emulsifying drug delivery systems (SMEDDS). While these technologies are widely used, they also have some limitations like recrystallization, which can occur during storage or gelation of the lipid suspension, amongst others.⁵ 

Polymers & Solid Dispersions 

Solid dispersions have become an accepted approach to improve the amorphous stability and increase the solubility of drug substances. These solid dispersions can be formulated as either polymeric delivery systems or non-polymeric delivery systems, the latter often prepared with synthetic amorphous silica. While polymeric solid dispersions are widely used, in many cases, re-crystallization of the API can occur more frequently during long-term storage due to higher molecular mobility as compared to silica-based solid dispersions. In a non-polymeric system, after an API is loaded into the porous network of amorphous silica particles, the formation of crystalline material is prevented by the confined space of the pores, which are only slightly larger than the API, thereby reducing the risk of molecular mobility during storage. 

Mesoporous Silicas for Improving Solubility and Bioavailability: 

The quest for better and new substances for solubility enhancement has also spurred innovation among other types of excipients, including amorphous synthetic silicon dioxides such as mesoporous silicas (MPS). These solubility enhancers have gained formulators’ attention due to their tunable porosity, high surface area, inertness, and good biocompatibility. The porous structure of silica can decrease the melting point and crystallinity of an entrapped drug.⁶ MPS has good flow properties and additional steps such as milling or sizing prior to tableting and capsule filling can often be simplified or eliminated. This results in high recovery rates and minimizes the chances of the processed drug converting to its crystalline state.⁷ 

Engineering the porosity, particle size, and surface properties of the silica enable MPS to be unique and versatile materials that are highly interesting to formulators as platforms for drug delivery. MPS can be synthesized by various routes with tight control of process parameters, and these impact the final product properties. Depending on the synthesis route and process conditions, the silica porosity (pore volume, pore size, and distribution) can be controlled precisely. The method of synthesis also dictates the concentration of surface hydroxyl groups on the silica. Taken together along with final particle size and distribution, these properties deliver an effective drug delivery solution. 

Approaches for Silica-based Drug Delivery System: 

APIs can be loaded onto the silica in two different approaches: 

1. Solvent impregnation method 
2. Ternary systems/hot melt extrusion (in early development) 

Solvent Impregnation Method 

W. R. Grace & Co. has conducted research and developed techniques for enhancing the solubility and hence the bioavailability of poorly soluble drugs using compendial silicas. Based on this research, solvent impregnation techniques (Figure 1) have been developed and entail the following: 

1. Dissolving a poorly water-soluble API in an organic solvent. Solvents such as ethanol, isopropanol, or acetone are usually suitable.
2. Impregnating the silica pores with the dissolved API and then evaporating the solvent.These steps can be achieved via several commercially available unit operations. A rapid mixer granulator, a spray dryer, or a fluid bed dryer can be used. This leads to a dry powder of the drug loaded in the pores of silica. 
3. Converting the silica loaded with drug substance into a solid oral dosage form such as a tablet or a capsule. 

To ensure that the drug substance is loaded effectively in the pores of the silica and to sufficiently suppress recrystallization, the impregnatio n must be processed under tightly controlled conditions. 

After an API is loaded into the porous network of amorphous silica particles, the formation of crystalline material is prevented by the confined space of the silica pores, which are slightly larger than the API, thereby reducing molecular mobility. The high internal surface area and hydrophilicity of MPS positively affects the wetting properties, which results in fast release profiles.⁷

Silicas in Ternary (Drug + Silica + Polymer) Systems Using Hot Melt Extrusion 

The combination of polymeric systems with silica can further enhance the solubility and bioavailability of APIs. Polymer- based ASD’s have several challenges such as hygroscopicity and recrystallization due to molecular mobility, while silica ASDs often lead to quicker API release in the GI tract that can be followed by API precipitation and recrystallization. However, these challenges can be resolved using the combination of both systems. Silica helps with moisture stabilization and reduces the risk of molecular mobility whereas polymers can help with controlling the release of the drug in the GI tract. 

Research is ongoing in this field. The key approach to formulate a ternary system is by using hot melt extrusion technology, which can offer a solvent-free method to enhance solubility and bioavailability of poorly soluble APIs.

After 20 minutes, the release profiles of both APIs are further enhanced compared to the pure API and a binary polymer system when formulated in a ternary system prepared using hot melt extrusion. The observed improvement in release is attributed to synergies between the components in the ternary system. 

Several technologies have been developed to increase the bioavailability of class II and IV APIs with low solubility in oral dosage forms. While there is no universal solution, each technology has its merits and shortcomings. 

Case Study: Fenofibrate 

A poorly soluble drug candidate, fenofibrate, was dissolved in ethanol at 30 wt.% concentration and impregnated into the pores of SILSOL® 6035 silica, which is an optimized grade of mesoporous silica. The solvent was then removed using rotovap, fluid bed dryer, and spray drying methods. The API stability measurements were carried out on the loaded silica systems after storage for 6 months at accelerated stability condition of 40°C and 75% RH using all three methods. Figure 2 and 3 show an example of the study using the rotovap method. Drug-loaded amorphous solid dispersions (ASDs) were characterized at different time intervals for assay, dissolution profiles, and polymorphic (amorphous to crystalline) conversions. X-ray diffraction (XRD) studies (represented in Figure 2) reveal that no crystallization occurred during stability testing.

Consistent drug release was also observed throughout the testing period. This demonstrates that an ASD system prepared using mesoporous silica, SILSOL® 6035 silica, and with the right pore size, can improve the stability and solubility of the drug. This is further evident from the release profile in Figure 3 as both impregnated samples achieved approximately ninety percent cumulative drug release after 30 minutes compared to less than ten percent for the pure crystalline fenofibrate.

References 

1. Williams RO III, Watts AB, Miller DA, “Formulating Poorly Water Soluble Drugs.” Spinger, New York (2012). 

2. Rahul Kumar, Amit Thakur, Pranava Chaudhari, et al, “Particle Size Reduction Techniques of Pharmaceutical Compounds for the Enhancement of Their Dissolution Rate and Bioavailability.” Journal of Pharmaceutical Innovation, 17, 333–352 (2022). 

3. Shery Jacob, Anroop B. Nair, “Cyclodextrin Complexes: Perspective from Drug Delivery and Formulation.” Drug Development Research, Volume 79, Issue 5, 201-217 (2018). 

4. Jason LePree, “LIPID-BASED DELIVERY – Are Lipid-Based Drug Delivery Systems in Your Formulation Toolbox?” Drug Development & Delivery, October 2017. https://drug-dev. com/lipid-based-delivery-are-lipid-based-drug-delivery- systems-in-your-formulation-toolbox/ 

5. Parisa Ghasemiyeh, Mohammadi-Samani Soliman, “Solid Lipid Nanoparticles and Nanostructured Lipid Carriers as Novel Drug Delivery Systems: Applications, Advantages and Disadvantages.” Research in Pharmaceutical Sciences, 13(4), 288-303 (2018). 

6. Michiel Speybroeck, Randy Mellaerts, Johan Martens, et al, “Ordered Mesoporous Silica for the Delivery of Poorly Soluble Drugs”. Controlled Release in Oral Drug Delivery, 203-219 ( 2011). 

7. Bruno Hancock and George Zografi, “Characteristics and Significance of the Amorphous State in Pharmaceutical Systems.” Journal of Pharmaceutical Sciences, Volume 86, Issue 1 (1997). 

8. Natalja Genina, Batol Hadi, Korbinian Löbmann, “Hot Melt Extrusion as Solvent-Free Technique for a Continuous Manufacturing of Drug-Loaded Mesoporous Silica.” Journal of Pharmaceutical Sciences, Volume 107, Issue 1 (2018).