Solubilizing the Insoluble

Improving the solubility of poorly water-soluble drugs is of crucial importance. As the number and diversity of molecules resulting from drug-discovery activities increases through methods such as combinatorial chemistry and high-throughput screening, scientists are faced with the task of developing formulations that may contain poorly soluble active pharmaceutical ingredients (APIs). The need for technical solutions to solubility problems has commercial implications for both pharmaceutical companies and their suppliers.

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The solubility of an API plays a crucial role in drug disposition because the main pathway for drug absorption is a function of permeability and solubility. Poor aqueous solubility is caused by two main factors: high hydrophobicity and highly crystalline structures. The aqueous solubility of a compound plays a role in its success or failure as a drug candidate. Better solubility results in better absorption in the gastrointestinal tract, reduced dosage-level requirements, and better bioavailability. In the development phase, poor solubility can lead to inadequate exposure in efficacy and toxicity studies. Higher dosages required to compensate for poor solubility can lead to side effects, food effects, and intersubject variability. It may drive up overall costs for drug development and production and lead to poor patient compliance because of the higher doses required to achieve a therapeutic effect. As pharmaceutical companies attempt to resolve these issues, contract-service providers and suppliers also are seeking to meet these challenges through targeted offerings.

Defining the challenge

The Biopharmaceutics Classification System (BCS), as forwarded by Amdion et al., categorizes compounds based on solubility and permeability (1). The BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability. When combined with the dissolution of the drug product, the BCS takes into account three major factors that govern the rate and extent of drug absorption: dissolution, solubility, and intestinal permeability. According to the BCS, drug substances are classified into four major classes:

• Class I: high permeability, high solubility

• Class II: high permeability, low solubility

• Class III: low permeability, high solubility

• Class IV: low permeability, low solubility (2).

According to a recent analysis, most new chemical entities (NCEs) are poorly water-soluble. Approximately 30% of marketed APIs are classified as BCS Class II compounds (i.e., high permeability and low solubility), and 10% of marketed APIs are classified as BCS Class IV compounds (low permeability, low solubility). For NCEs under development, the level of drugs that may be classified as poorly water-soluble increases. Approximately 70% of NCEs under development may be classified as BCS Class II compounds (i.e., high permeability and low solubility), and 20% of NCEs are classified as BCS Class IV compounds (low permeability, low solubility) (3).

Solubilization strategies

Both physical and chemical methods can be used to improve drug solubility, explains Firouz Asgarzadeh, principal scientist at Evonik Degussa (Piscataway, NJ). Asgarzadeh was a panelist on an educational webcast on pharmaceutical melt extrusion held by Pharmaceutical Technology in September 2010. Chemical methods to improve solubility include developing more soluble prodrugs or improving solubility through salt formation. Physical methods include micronization or nanosizing, producing a polymorph, changing the crystal habit, complexation, solubilization through self-microemulsifying drug-delivery systems, and solid dispersions.

Solid dispersions/solid solutions

The terms solid solution and solid dispersion define related compositions in which at least one active ingredient is dispersed in an inert matrix. In solid dispersions, separate regions of drug and polymer exist throughout the matrix, and the drug may be crystalline or be rendered in its amorphous state. A special subset of solid dispersions, solid solutions, refers to the case in which drug–polymer miscibility is attained at the molecular level, and the drug exists in its amorphous form. Pharmaceutical polymers are used to create this matrix. Polymer selection is based on many factors, including physicochemical (e.g., drug–polymer miscibility and stability) and pharmacokinetic (e.g., rate of absorption) constraints (4).

Solid dispersions may be made through mechanical activation (i.e., cogrinding), coprecipitation, freeze drying, spray drying, melt extrusion, and KinetiSol technology (DisperSol Technologies, Austin, TX), a fusion-processing technology. The solid-dispersion components consist of the API, the polymer, plasticizers, stabilizers, and other agents, explains Asgarzadeh. Various polymers may be used in solid dispersions. These include methylacrylate polymers, polyvinyl acetate, polyvinylpyrrolidone, copovidone, poly-(ethylene-vinylacetate-vinylcaprolatam), and cellulose derivatives (e.g., hypromellose acetate succinate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl cellulose, and methyl cellulose).

When developing solid-dispersion formulations of poorly soluble APIs, one may compare the API functional groups with the polymer functional groups, compare the API solubility parameters with polymer–solubility parameters, and analyze the expected permeability of the API to determine which polymers to evaluate for solid-dispersion technology (4). Additional factors such as the API permeability window, polymer supply, polymer toxicology, physical-product characteristics, and processing yields are also factors that have to be considered during product development (5).

The pharmaceutical plasticizers used in hot-melt extrusion may be used for various applications, explains Asgarzadeh. They can be used to reduce glass-transition temperature and melt viscosity, to lower processing temperature, to improve flexibility, and to improve extrudate surface appearance (i.e., smoothness). Examples of plasticizers that may be used in these applications are triethyl citrate, low-molecular weight polyethylene glycols, dibutyl sebacate, propylene glycol, diethyl phthalate, dibutyl phthalate, and glycerol monostearate.

As with any pharmaceutical formulation, a key consideration in the development of a hot-melt extrusion formulation is to evaluate whether the API, the polymer, and other ingredients will be effective in a given formulation. "By predicting compatibility and miscibility, it can be checked if the drug, polymer, or other ingredients fit together," says Asgarzadeh. "This prediction can reduce the number of feasibility experiments, thereby saving time, the amount of API used in studies, and the cost of such studies."

Predictive modeling. Solubility parameters can predict possible interactions between a drug molecule and the polymers used in a hot-melt extrusion application. Miscibility can be evaluated quantitatively and qualitatively. A qualitative evaluation excludes hydrogen-bonding capability. A quantitative estimation involves estimating the solubility parameter, which is a function of non-hydrogen-bonded parameters and hydrogen-bonded parameters. "For non-hydrogen-bonded parameters, the question being asked is: Will dispersive forces lead to an one-phase system?" says Asgarzadeh. "For hydrogen-bonded parameters, the question being asked is: Are hydrogen bonds involved to avoid crystallization?"

Evonik has developed a system, Melt Extrusion Modeling and Formulation Information System (MEMFIS), as a predictive modeling tool in developing a hot-melt extrusion formulation. MEMFIS helps in selecting initial formulations with no API consumption, using mathematical models and algorithms based on solubility parameter theories (i.e., hydrogen bonding and polar and dispersive forces). MEMFIS uses chemical structures, solubility parameters, physicochemical properties, and a myriad of processing conditions to suggest initial formulation components and process settings for a hot-melt extrusion formulation.

In terms of miscibility estimation, for example, MEMFIS evaluates which excipients have higher potential to form a solid solution by assessing the drug miscibility of a given excipient in comparison to other excipients. The qualitative method, (i.e., which excludes hydrogen-bonding capability in the evaluation) considers the drug miscibility with an excipient in comparison to other excipients to make the determination of whether one excipient is more or less miscible. Only dispersive interactions are considered. Qualitative-only methods may lead to the exclusion of valuable excipients from the screening studies that could potentially form strong hydrogen bonds with the APIs.

In the quantitative evaluation in the MEMFIS, which is a deeper analysis, in addition to polar and dispersive interactions, the specific possible hydrogen-bonding interactions are investigated at a molecular level to derive a quantitative expectation in terms of drug–excipient miscibility in a binary system. In this quantitative assessment, additional specific hydrogen-bonding capability is considered. This involves considering polymers from a monomer perspective (i.e., meaning the composition of the polymer) and specifying the type of hydrogen bonding that could be involved and its impact on the solubility parameters. "Solubility-parameter estimation and molecular-interaction considerations are powerful tools in estimating first formulations in solid-dispersion product development," says Asgarzadeh. "High- throughput screening is accomplished based upon molecular structure, intra- and inter-molecular bonding, and their impact on solubility parameters."

Commercial examples. Several commercial products use solid solutions or solid dispersions. One example is a solid dispersion of crystalline griseofulvin in polyethylene glycols (gris-PEG), which cut the crystalline 500-mg dose in half while maintaining plasma concentrations. Another example is the antiemetic Cesamet (nabilone) (Valeant Pharmaceuticals, Costa Mesa, CA), which contains a solid dispersion of nabilone in polyvinylpyrrolidone. Solid solutions of lopinavir and ritonavir in polyvinylpyrrolidone–vinyl acetate copolymer enabled a reformulation of Kaletra (Abbott Laboratories, Abbott Park, IL). Sporanox (Janssen Pharmaceutica, Titusville, NJ) is a solid dispersion of itraconazole in hypromellose that has been layered onto sugar spheres. The nonnucleoside reverse transcriptase inhibitor Intelence (Tibotec, Yardley, PA), is an amorphous, spray-dried solid dispersion of etravirine, hypromellose, and microcrystalline cellulose (4).

Charting industry developments

Several companies have recently announced developments supporting activities for solid dispersions and other approaches in their toolbox to tackle the problem of solubility. In addition to MEMFIS, Evonik is positioned in solid-dispersions through its methylacrylate polymers (Eudragit). Several late-stage products have been developed with these excipients in solid-solution formulations. Evonik has hot-melt extrusion and spray-drying capabilities in the United States, Germany, and India, as well as spray-drying capabilities in Japan. In 2009, Evonik partnered with the contract manufacturer Rottendorf Pharma (Ennigerloh, Germany) for capabilities in hot-melt extrusion.

In October 2009, International Specialty Products (ISP, Wayne, NJ) launched a drug-solubility initiative to support pharmaceutical companies working with drug actives that exhibit poor solubility. The initiative focuses on solubilization technologies that involve excipients, formulation, and related processing services, which includes solid-dispersion technology, both hot-melt extrusion and spray drying. ISP has been engaged in the formulation of spray-dried solid dispersions since 2004 and has developed formulations for approximately 100 compounds during that time through its contract-research division. In 2009, ISP partnered with the equipment manufacturer Coperion (Stuttgart, Germany) for advancing hot-melt extrusion technology by providing ingredient technology in polymers and disintegrants as well as expertise in material science. Coperion is providing equipment for testing and knowledge of the physical systems used in extrusion.

As part of its solubility initiative, ISP is also emphasizing ingredient technology such as cyclodextrins and disintegrants."Drug–cyclodextrin inclusion complexes are well known to increase solubility and enhance bioavailability," said Tim Bee, senior global technical director of pharmaceuticals at ISP, in an Oct. 5, 2010, press release issued at CPhI Worldwide in Paris. Cyclodextrins are bucket-shaped oligosaccharides with a hydrophobic cavity and hydrophilic exterior. Given their molecular structure and shape, cyclodextrins function as molecular containers by entrapping guest molecules such as APIs within the internal cavities. This structure–function relationship can produce formulation advantages that include the ability to increase the solubility of poorly soluble drug actives. As part of an alliance with Wacker-Chemie (Munich), ISP markets and provides technical support for cyclodextrin products.

Also at CPhI last month, ISP announced that it will launch a high-purity crospovidone (Polyplasdone Ultra and Polyplasdone Ultra-10) in November 2010 as part of its toolkit for increasing the bioavailability of poorly water-soluble drugs. The product will be manufactured at its facility in Texas City, Texas. ISP recently published results of a study demonstrating the solubilization benefits of Polyplasdone crospovidione in formulations of poorly water-soluble drugs (6).

Other companies are emphasizing their technology for solid dispersions. BASF (Ludwigshafen, Germany) was recognized for innovation at CPhI for its excipient, Soluplus, which is used in hot-melt extrusion applications. BASF launched the polymeric solubilizer in 2009. Earlier this year, BASF partnered with the equipment manufacturer GEA Niro (Søborg, Denmark) to allow BASF to make in accordance with current good manufacturing practice spray-drying tests and pilot productions of APIs at GEA's test station in Copenhagen. Dow Wolf Cellulosics (Horgen, Switzerland) offers several expicients for hot-melt extrusion applications, including poly (ethylene) oxide resins (e.g., Polyox) and cellulosic derivatives [e.g., Ethocel (ethylcellulose ethers) and Methocel (cellulose ethers)].

In September 2010, Bend Research (Bend, OR), a formulation development and manufacturing company, expanded manufacturing capabilities for hot-melt extrusion. The company purchased intermediate-scale equipment, an 18-mm extruder, to complement existing extruder capacity of 7.5 mm and 27 mm. The three extruders enable scale-up of a formulation from small-scale development work through large-scale manufacture of clinical supplies.

LifeCycle Pharma (LPC, Hørsholm, Denmark), an emerging speciality pharmaceutical company that was spun off from the pharmaceutical company H. Lundbeck (Copenhagen) in 2002, bases its business model on taking marketed drugs that are poorly water-soluble and applying a proprietary technology (MeltDose) to improve bioavailability. The company has patented a controlled-agglomeration process, which works by incorporating the drug substance with low water-solubility into a meltable vehicle. The drug is then sprayed on an inert particulate carrier using fluid-bed equipment. The melt is solidified when deposited on the particle carrier, thereby capturing the active drug in a solid dispersion either as a solid solution or in a nanocrystalline state. The particle size is increased by controlling and optimizing the product temperature and feed rate (7). The company is using this approach as opposed to other drug-delivery technologies, which seek to increase bioavailability of compounds with low water solubility through reduction of the particle size of the drug substance, which increases the surface area available for dissolution.

LCP has one commercial product that uses the MeltDose technology, Fenoglide (fenofibrate), which is marketed in the United States as a treatment for hyperlipidemia and mixed dyslipidemia. The company's lead pipeline candidate is LCP-Tacro (tacrolimus), currently in Phase III trials, to treat immunosuppression in kidney and liver transplantation. It is also developing two other products: LCP-AtorFen, a fixed-dose combination tablet of fenofibrate and atorvastatin, and LCP-Feno, a generic 145-mg fenofibrate tablet.

Advances from academia

Researchers at the University of Texas at Austin and DisperSol Technologies recently reported on thermal production methods for the production of solid dispersions without the use of plasticizers. Plasticizers are typically needed to achieve the required molten material-flow properties when using unit operations such as hot-melt extrusion. The technology, KinetiSol, a high-energy thermal manufacturing process, was applied to produce amorphous solid dispersions without the aid of a plasticizer. The model active ingredient examined in the study was itraconazole (8).

Poor solubility is particularly problematic when developing anticancer therapeutics because the goal is to achieve clinical efficacy while limiting the dosage of chemotherapeutic agents. To address this issue, researchers at Northwestern University in Evanston, Illinois, recently reported on using nanodiamond-mediated delivery for several water-insoluble drugs. In their study, the researchers reported that nanodiamonds were used to enhance the water dispersion of three anticancer agents: purvalanol A, a treatment for liver cancer; 4-hydroxytamoxifen, a drug to treat breast cancer; and dexamethasone, an antiflammatory agent to treat complications from certain types of cancer (9, 10).

The researchers showed that the water-insoluble compounds interact with the nanodiamonds, a biocompatible material, and formed complexes capable of dispersing the drug in water for sustained periods of time while maintaining the functionality of the drug. The researchers used ultraviolet–visible spectrophotometry, transmission electron microscopy imagery, and zeta potential measurement via dynamic light-scattering analysis to confirm the complexation of the water-insoluble compounds with the nanodiamonds and used methylthiazol tetrazolium and DNA-fragmentation assays to confirm that the functionality of the drugs was maintained (9, 10). Nanodiamonds are a class of nanomaterials 4–6 nm in diameter in single-particle form, which can be manipulated to form clusters with diameters in the range of 50–100 nm, according to the Nanoscale Biotic-Abiotic Systems Engineering Laboratory at Northwestern University. This composition makes them suitable for drug delivery by shielding and slowly releasing drugs that are trapped within the cluster of the diamond aggregates. Benefits in drug delivery from the nanodiamond cluster include the capability of trapping more drug in the nanodiamond cluster compared with conventional drug-delivery methods and facile dissolution of the nanodiamonds in water. Nanodiamond surfaces are functionalized with carboxyl groups to enhance their dispersibility in water. Previous studies showed that the surface electrostatic properties of nanodiamonds can promote potent water binding, thereby further enhancing material dispersibility in water (9, 10).

References

1. Amdion et al, Pharm Res 12 (3), 413–420, 1995.

2. FDA, Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System (Rockville, MD, Aug. 2004).

3. C.Y. Wu and L.Z. Benet et al., Bull. Technique Gattefosse 99, 9–16 (2006).

4. J. Doney and J. Yang, Pharm. Technol. 32 (7), 96–98 (2008).

5. T. Bee and M. Rahman, Pharm. Technol. 34 (9), CPhI/ICSE Supp. s37–s42 (2010).

6. J. Balasubramaniam and T. Bee, Pharm. Technol. 33 (4) Excipient Performance for Solid Dosage Forms Supp., s6–s14 (2009).

7. P. Holm et al., "Controlled Agglomeration," US patent 7217431, May 15, 2007.

8. J.C. DiNunzio et al., Eur. J. Pharm. Sci. 40 (3), 179–187 (2010).

9. P. Van Arnum, Pharm. Technol. 34 (1), 48 (2010)

10. D. Ho, et al., ACS Nano 3 (7), 2016–2022 (2009).