BIOAVAILABILITY ENHANCEMENT - Solving Low Solubility Challenges to Optimize Drug Delivery Platforms 

INTRODUCTION

Low aqueous drug solubility in pharmaceutical pipelines is a pervasive issue. In particular, rapidly growing therapeutic areas, such as oncology, anti-virals and anti-inflammatory indications, are largely plagued by small molecule drugs with low solubility and bioavailability. It is estimated that 70% to 80% of pipeline drugs in development today are poorly soluble molecules.¹ As a result, a number of enabling technologies have been developed to improve oral drug absorption and bioavailability (BA). Com­monly used technologies in this area have been extensively re­viewed and include salts, cocrystals, amorphous solid dispersions (ASDs), nano and micro-crystals manufactured by particle size reduction, cyclodextrin complexation, and lipid-based technolo­gies.²

For instance, salt formation for solubility enhancement is a common technique used during solid form selection for ionizable compounds.³ However, many salts form hygroscopic materials that can lead to both physical and chemical stability issues. In ad­dition, many salts do not substantially enhance a poorly soluble compound’s bio performance because of precipitation of the compound in the presence of food (increased pH), common ions in the stomach, or as the pH increases upon transfer into the duo­denum.

For the more than 50% of the compounds in development that are either not ionizable or suffer from stability issues as a salt form, alternative solubility enhancing technologies are needed. Many technologies have been shown to enhance drug BA; how­ever, the most notable commercial products are those that utilize lipid-based technologies, ASDs, and micronized crystals. The commercial precedence of these key enabling technologies sup­ports their continued utilization in addressing the new chemical entities (NCEs) development pipeline candidates that are re­garded as poorly water-soluble.

The following discusses how low aqueous solubility NCEs have come to define the innovative pharmaceutical pipelines and how advanced technologies are often required to overcome this issue. It further defines how bioavailability enhancing (BAE) tech­nology selection can aid in defining an optimized delivery plat­form. Finally, the most prominent BAE technology (ASDs) is described with some novel twists to overcome a relatively new problem — molecules that have both low aqueous and organic solubility.

EARLY PHASE PROCESS DEVELOPMENT – IMPROVING COMMERCIAL OPPORTUNITY

A recent trend in the earlier phases of drug development is the low aqueous solubility of NCEs. Among the varying formula­tion strategies that can be used to improve solubility, ASDs have been the most frequently used technology from 2000 to 2020 (Figure 1).

The most common technique for the manufacture of ASD systems is spray drying. Spray drying is the technology of choice due to its fast-drying rate, ability to kinetically trap the drug in amorphous form, scalability, and broad applicability across dif­ferent target drug profiles.⁵

The spray drying process begins with a solvent, the API, and polymer in a solution tank. A high-pressure pump then pushes the solution through either a two-fluid or pressure swirl nozzle into the top of the spray dryer, creating droplets that are met with a heated nitrogen and then formed into solid particles that are trapped in the amorphous phase. Next, the nitrogen gas and solid particles flow into a cyclone where the ASD is collected. When spray drying at a small scale, the nitrogen is sent to a scrubber and vented; however, at a large scale, the spent nitrogen has some residual solvent, which is condensed into a residual solvent stream as liquid waste, and the nitrogen is recycled back into the dryer as a closed loop.

For this process to yield an amor­phous product, all the components that begin in the solution tank must be fully dissolved before spray drying manufactur­ing. However, the increased number of NCEs that have poor solubility in water and organic solvents can make this espe­cially challenging. Low organic solubility, in particular, can lead to small particles that can negatively impact downstream processing due to poor flow properties making capsule filling or tableting difficult. Likewise, it can create non-economic processes at a commercial scale due to low throughputs. Early phase developers may try to overcome this by designing a process based on low solid concentration in a pre-clinical or Phase 1 manufacturing process or by using solvents, such as dichloromethane (DCM) or tetrahydrofu­ran (THF), in which these NCEs are more soluble. Yet, each of these approaches can compromise a commercial line-of-sight when the early phase studies are success­ful. In particular, these solvents are more toxic than conventional spray-drying sol­vents. DCM presents significant environ­mental risks, resulting in emissions that are increasingly regulated, thus limiting production. In addition, THF has the risk of peroxide formation, which can cause chemical degradation in a product and increase the risk of explosions. Both sol­vents present potential equipment incom­patibility.

INCREASING SOLVENT SOLUBILITY USING HEAT

An alternate approach to increasing solubility in conventional spray-drying sol­vents is the application of heat to the spray solution. There are two methods in which heat can be used to increase solubility. The first is a warm process, in which a jacketed tank is heated to a temperature below the boiling point of the solvent to dissolve the drug, thereby increasing solubility. The re­mainder of the process is the same, using standard nozzles and conventional pro­cessing conditions.

The second method is a temperature shift process. With this approach, a slurry of undissolved drug is pumped to the top of the spray dryer and then run through an inline heat exchange, which rapidly in­creases the temperature of the solution to above the boiling point of the solvent to dissolve the drug. The solution is then pumped into the drying chamber, where a flash nozzle is used to atomize the solu­tion. At Lonza, we designed a flash atom­izer to take advantage of the solution flashing or boiling as it’s going into the chamber.

The first case study looks at the use of temperature shift technology. The graph in Figure 2, where the X-axis is organic solu­bility in methanol (MeOH) or acetone, and the Y-axis is the solubility of the drug, shows three groups of compounds:

Group I has sufficient solubility in Lonza’s preferred spray-drying solvents, making them a reliable option during spray drying to create an ASD.

Group II has low organic solubility and a low melting point. Hot melt extru­sion is a good approach for these com­pounds, although spray drying could be used as well.

Group III are brick dust compounds and therefore, have low organic solubility in MeOH or acetone. They also have ex­tremely high melting points, which means they require an innovative spray during or thermal processing technique.

In order to achieve high throughput at commercial scale, the targeted drug weight percentage (wt%) is at least 1 wt%. When using a standard spray-drying process for alectinib HCL, only 0.125 wt% drug concentration was achieved with a solution temperature of 25°C compared to 1 wt% and 1.8 wt% (noted in blue dots in Figure 3) when heating the solution to 130°C to increase solubility (temperature shift method). This represents an 8- to 14-fold increase in solubility and, therefore, throughput. Furthermore, there is also the estimated difference in processing time between spray drying and the temperature shift method. Conventional spray drying takes more than 100 hours to manufac­ture 4 kg at clinical scale, which would re­quire operators working multiple 12-hour shifts. Conversely, the temperature shift method totals less than 15 hours for 1 wt% for the same scale. In addition to these benefits and a decrease in solvent con­sumption, using heated solvents is an im­provement when compared to solvents that have negative environmental impacts.

INCREASING SOLUBILITY USING PROCESSING AIDS

Generally, salt formation is a com­mon and effective method for increasing solubility and dissolution rates of acidic and basic drugs.3 When the salt form is not stable enough or does not enhance bio performance sufficiently, it may be necessary to use an ASD. If the low aque­ous soluble compound is also poorly sol­uble in organic solvents, alternate techniques may be required. An alterna­tive approach is to use volatile aids to ionize a drug in an organic solvent in the so­lution tank. Because the aid is volatile, it’s removed during the spray-drying and secondary drying processes, leading to reformation of the ingoing form of the API. This approach does not require any addi­tional steps and can be used with existing equipment.

ACETIC ACID

In the first case study of volatile aids, acetic acid is used as a processing aid. The model compound is gefitinib, which has a basic acidic strength (pKa) of 7.2 while acetic acid has a pKa of 4.75. By adding a minimal amount of acetic acid, it in­creases the solubility 10-fold when com­pared to adding only methanol (MeOH) and water (H2O) (Figure 4).

As a result, gefitinib was successfully spray dried using a selection of typical ASD polymers, demonstrating this method can be used with a variety of polymers (neutral and enteric) and there are mini­mal limitations to excipient choice. Further­more, conventional spray- dry conditions were used for the remainder of this process. This volatile aid does not impact viscosity nor does it require higher input dryer temperatures.

All of the dispersions had the same performance and morphology compared to controls, showing that inclusion of the volatile aid does not affect the final prod­uct. Additionally, all of the acidic acid was removed below ICH limits during tray dry­ing, so the ingoing form of the drug sub­stance was regenerated.

AMMONIA

In addition, ammonia was used in the second case study of volatile aids. Analo­gous to the acetic acid processing aids, ammonia works for weakly acidic com­pounds. Ammonia’s basic pKa is 9.25. Two different model compounds were used for this case study: piroxicam (pKa 4.7) and sulfasalazine (pKa 3.2). An ammonia concentration of more than one molar equivalent was added in, so all of the API was fully protonated. Our results showed a 20-fold increase in solubility for piroxi­cam and a 40-fold increase for sul­fasalazine.

Piroxicam was spray dried using se­lect ASD polymers, again demonstrating the ability to use a variety of polymers (neutral and enteric). Conventional condi­tions were used for the remainder of the process.

The use of volatile aids to increase solubility should be used if the compound is poorly soluble in acetone or MeOH (pre­ferred spray-drying solvents) and when the compound is ionizable. Figure 5 repre­sents internal data from Lonza showing compounds that are ionizable and when this methodology would be applicable.

The use of warm and temperature shift processes as well as volatile aids to increase solubility for low aqueous and or­ganic soluble compounds not only reduce manufacturing time, which can ultimately save time and money, but also eliminate the use of solvents that are harmful to the environment and, potentially, the health of facility personnel.

SUMMARY

NCEs with low aqueous solubility have come to dominate the pharma pipelines. There are a number of technolo­gies that have been demonstrated to be capable of improving solubility and, hence, bioavailability. However, ASDs manufactured by spray drying have be­come a mainstream approach to over­coming the significant fraction of pipeline molecules that have poor aqueous solubil­ity and bioavailability. This technology has become prevalent due to its fast-drying rate that enables kinetic trapping of the drug in amorphous form and scalability and broad applicability. Spray drying has also evolved to allow processing of com­pounds that are insoluble in both aqueous and organic systems, broadening its ap­plicability and improving its commercial applicability.

REFERENCES

1. Moreton, Chris, Ph.D. (February 18, 2021). American Pharmaceutical Review. Poor Solubility ― Where Do We Stand 25 Years After The ‘Rule of Five’? https://www.americanpharmaceuticalre­view.com/Featured-Articles/573402-Poor-Solubil­ity-Where-Do-We-Stand-25-Years-after-the-Rule-of-Five/.
2. H.D. Williams, N.L. Trevaskis, S.A. Charman, R.M. Shanker, W.N. Charman, C.W. Pouton, and C.J. Porter. Pharmacological Reviews. 65:315 (2013).
3. D. Gupta, D. Bhatia, V. Dave, V. Sutariya, and S. V. Gupta, Molecules. 23(7): 1719 (2018).
4. Iyer, Raman, et. al. Amorphous Solid Dispersions (ASDs): The Influence of Material Properties, Man­ufacturing Processes and Analytical Technologies in Drug Product Development. Pharmaceutics, 13(10), 1682 (2021). https://doi.org/10.3390/pharmaceutics13101682.
5. Na Li, Jonathan L., et. al. (September 15,. Molec­ular Pharmaceutics, 17(10), 4004-4017 (2020). https://pubs.acs.org/doi/10.1021/acs.molphar­maceut.0c00798.

Dr. David Lyon serves as a Senior Fellow, Global R&D, at Lonza’s site in Bend, OR, where he advises on internal and external collaborations for bioavailability enhancement technologies, modified release, and bioprocessing. He joined Bend Research as a Research Chemist in 1991. During his tenure at Bend Research, he held positions of increasing responsibility, leading numerous large-scale research programs and ultimately being named Senior Vice President, Research prior to the company’s acquisition by Capsugel and, subsequently, Lonza. His areas of expertise include extensive work with amorphous solid dispersions for bioavailability enhancement of active compounds with low aqueous solubility, as well as the development of modified- release formulations and bioprocesses. He earned his Bachelor of Science degree in Chemistry from Western Washington University and his PhD in Inorganic Chemistry from the University of Oregon. Subsequently, he completed postdoctoral work at the California Institute of Technology.