Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

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 (1). As pharmaceutical companies attempt to resolve these issues, contract-service providers and excipient suppliers are seeking to meet these challenges through targeted offerings. 

Both physical and chemical methods can be used to improve drug solubility, 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 (1). 

 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 (1, 2). 

Solid dispersions may be made through mechanical activation (i.e., cogrinding), coprecipitation, freeze drying, spray drying, melt extrusion, and KinetiSol technology (DisperSol Technologies), a fusion-processing technology. The solid-dispersion components consist of the API, the polymer, plasticizers, stabilizers, and other agents. 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) (1). 

Hot-melt extrusion is used to disperse APIs in a matrix at the molecular level to form solid solutions and is used as a method to improve solubility of poorly water-soluble drugs (3). Evonik has developed a system, Melt Extrusion Modeling and Formulation Information System (MEMFIS), as a predictive modeling tool in developing hot-melt extrusion formulations. 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 (1). 

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 (1). 

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 important tools in estimating first formulations in solid-dispersion product. High-throughput screening is accomplished based upon molecular structure, intra- and inter-molecular bonding, and their impact on solubility parameters (1). 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 both hot-melt extrusion and spray-drying capabilities. 

Other companies are advancing their hot-melt extrusion capabilities. In October 2011, Ashland Specialty Ingredients, which acquired International Specialty Products (ISP) in 2011, announced it was adding a GMP hot-melt extruder at its Columbia, Maryland, R&D center to better serve pharmaceutical companies working with poorly soluble drug compounds. The 180-mm Leistritz extruder allows companies that seek to commercialize drugs, which are made more soluble with dispersions from Ashland, to scale up to GMP clinical and commercial quantities produced by hot-melt extrusion. Ashland planned to finish installing and testing the equipment in the fourth quarter of 2011 and to begin a full-service offering early in 2012. The company has an existing extruder at its Wilmington, Delaware Research Center. With the addition of the extruder, Ashland is able to conduct kinetic-solubility and polymer-screening tests using both spray drying and hot-melt extrusion techniques to determine the best solubility solution in clinical trials. In October 2009, ISP launched a drug-solubility initiative that focused on solubilization technologies that involved excipients, formulation, and related processing services, which included solid-dispersion technology, both hot-melt extrusion and spray drying. In 2009, ISP partnered with the equipment manufacturer Coperion for advancing hot-melt extrusion technology. 

Thin-film technology advances as a specialized oral dosage form			

In February 2012, the CDMO Bend Research formed a licensing agreement with Eli Lilly under which Lilly gains access to Bend's proprietary spray-dried dispersion technology, which is designed to improve the bioavailability of compounds with low aqueous solubility. In addition, as part of an already existing agreement with Lilly, Bend Research will continue to provide formulation, development, analytical, engineering, and manufacturing services to Lilly to support its preclinical and clinical development programs. In August 2011. Bend Research also formed a collaboration with the CDMO Xcelience for oral solid-solubilization formulation solutions and clinical-supply manufacture. 

In July 2011, the CDMO Pharmaceutics International (Pii) added hot-melt extrusion to its formulation and process-development solutions capabilites. The company purchased a 16-mm and an 18-mm Leistritz twin-screw extruders. This investment enables Pii to carry out feasibility studies to pilot-scale cGMP productionfor Phase I and II clinical-trial materials using hot-melt extrusion. 

Emerging technologies: oral peptide delivery			

In 2009, BASF launched its polymeric solubilizer, Soluplus, which is used in hot-melt extrusion applications. In 2010, the company partnered with GEA Niro to allow BASF to make cGMP spray-drying tests and pilot productions of APIs at GEA's test station in Copenhagen. Dow Wolf Cellulosics 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 April 2011, the CDMO Pharmatek Laboratories added spray drying to its drug formulation and manufacturing capabilities. The company purchased a Buchi B-290 Mini Spray Dryer for formulation feasibility studies and small-scale clinical manufacture.  

Researchers at Purdue University recently reported on an  extrusion-based approach where the dissolution rate of poorly soluble drugs (griseofulvin, phenytoin, and spironolactone) was improved through solid crystal suspensions. The drug and mannitol were coprocessed in a hot-melt extrusion operation. The resulting product was a mixture of the crystalline drug and

crystalline excipient, with up to 50% (w/w) drug load. The 

 drug release from the obtained solid crystalline suspensions was more than two orders of magnitude faster than that of the pure drug. The researchers reported that because the resulting product was crystalline, the accelerated dissolution rate did have the physical stability concerns as with amorphous formulations. The researchers reported this approach is useful in situations where the drug is not a good glass former or in cases where it is difficult to stabilize the amorphous drug (4).  

Articles

Pharmaceutical companies, equipment providers, contract-service providers, and excipient manufacturers apply various approaches for improving solubility. The article examines some recent developments.

Meeting Solubility Challenges

Taste-masking of solid dosage and liquid drugs is a challenge for pharmaceutical manufacturers. Most APIs are unpleasant or harsh tasting leading to patient noncompliance. This challenge affects all age groups, but is specifically problematic for pediatric patients. The global market for pediatric drugs and vaccines is forecast to reach $85 billion by year 2017, according to data from Global Industry Analysts. The US is the largest market for pediatric drugs followed by Western Europe. Implementing taste-masking programs into the drug-manufacturing process is crucial to avoid losses due to noncompliance. Pharmaceutical manufacturers are faced with challenges in life-cycle management, cost control, global regulations, and patent protection.  

 examined formulation-development strategies in product life-cycle management, including specialized formulations such as pediatric formulations, and the specific technical issues that may evolve in excipient selection and functionality, including taste-masking and moisture protection, to develop an orally palatable product.  

Participating in the webcast were: Avinash Thombre, PhD, research fellow, pharmaceutical sciences with Pfizer Global Research and Development, who discussed life-cycle management and new dosage form options; Karen C. Thompson, PhD, distinguished senior investigator, pharmaceutical sciences at Merck & Co., who discussed insight into pediatric formulations and related dosage forms; and Nigel Langley, PhD, MBA, head of North American technical sales, Pharma Ingredients & Services, BASF, who discussed novel taste-masking excipient solutions. The webcast may be found at 

Taste-masking in Formulation Development.

In 2011, BASF launched Kollicoat Smartseal 30 D, an aqueous  disperson of a film-forming polymer with taste-masking and moisture-barrier applications. The excipient is highly impermeable to water vapor, which helps preserve the potency of sensitive active ingredients, according to the company.  The polymer is stable in saliva and specifically soluble in gastric juice. These properties allow for effective protection from unpleasant taste in the patient's mouth and rapid release and onset of active ingredient action in the stomach. 

In October 2011, BASF and Colorcon announced a collaboration for the development of future film-coating systems using BASF's Kollicoat Smartseal 30 D and a new Colorcon preformulated additive. Colorcon developed the preformulated additive system for use with Kollicoat Smartseal 30 D to enable efficient preparation and application of this polymer in taste-masking applications. The preformulated additive lowers the number of materials to be dispensed by 50% and reduces the preparation time by almost 40%, according to an Oct. 21, 2011, BASF press release.  

"We have chosen Kollicoat Smartseal 30 D because it is the best-in-class reverse enteric polymer for taste masking", said Kamlesh Oza, general manager, film coating at Colorcon, in the BASF press release. "Kollicoat Smartseal 30 D is the first water-based dispersion having both taste-masking and moisture-barrier properties. It was developed to simplify and accelerate aqueous film coating operations and opens new doors for formulating tablet, pellet, and particle coatings. Our collaboration to develop the additive will bring batch-to-batch color consistency, performance, speed, and simplicity, enabling easy reconstituting of the film former in pharmaceutical coating operations while maintaining functionality," he said.  

Kollicoat Smartseal 30 D is part of BASF's existing tablet coatings portfolio. Under the Kollicoat brand, BASF markets a range of coating polymers and copolymers that are used to coat tablets, capsules, and pellets and to control the release of drugs from solid-dosage forms. The Kollicoat family includes: Kollicoat IR and Kollicoat Protect instant-release coatings, Kollicoat IR Color Coating Systems, Kollicoat MAE enteric coatings, Kollicoat SR 30 D sustained-release coatings, and the new Kollicoat Smartseal 30 D protective coatings. 

Taste-masking is an important consideration to ensure patient compliance.

Advances in Taste-masking

Although the problem of counterfeit drugs traditionally has centered on solid dosage drugs, recent drug shortages for injectable cancer medications have triggered concerns over counterfeit versions of these types of drugs. In January 2012, FDA advised that current shortages of injectable cancer medications may present an opportunity for introduction of non-FDA approved products into the drug supply. FDA advised healthcare providers to obtain and use only FDA- approved injectable cancer medications purchased directly from the manufacturer or from wholesale distributors licensed in the United States. 

This article was also published in our US sister publication 

Regulatory bodies, standard-setting organizations, and industry seek to tackle the problem of counterfeit drugs and securing the flow of pharma ingredients.

Securing the Pharma Supply Chain

GlaxoSmithKline is recalling 394,230 bottles containing its antihypertensive drug DynaCirc CR (isradipine) controlled-release tablets, according to a Feb. 22, 2012, FDA 

. The lots are being recalled due to concerns regarding the level of cGMP compliance and procedural controls related to line clearance during the packing process at the Lincoln, Nebraska, facility of Novartis Consumer Health, where the product is made.

DynaCirc CR (isradipine) controlled release tablets, 5 mg, 30-count bottles, Rx only; NDC 0173-0784-01; UPC 3 0173-0784-01 8. Recall # D-1212-2012;

DynaCirc CR (isradipine) controlled release tablets, 10 mg, 30-count bottles, Rx only; NDC 0173-0785-01; UPC 3 0173-0785-01 5. Recall # D-1213-2012

Lot #: 10084536, Exp 12/12; 10102915, Exp 03/13; 10102916, Exp 06/13; 10107157, Exp 07/13; and 10108172, Exp 09/13;

Lot #: 10087732, Exp 01/13; 10091069, 10094639, Exp 03/13; 10102913, Exp 07/13; and 10109327, Exp 10/13

In January 2012, Novartis Consumer Health issued a voluntary recall of lots with select bottle packaging configurations for several of its over-the-counter products (Excedrin, NoDoz, Bufferin, Gas-X Prevention), sold in the United States and manufactured at its Lincoln facility. Novartis initiated the recall because the products may have contained stray tablets, capsules, or caplets from other Novartis products, or contained broken or chipped tablets.

At the time of the recall in January, Novartis temporarily suspended operations and shipments from the site. Novartis said it planned to gradually resume operations at its Lincoln site following implementation of planned improvements and in agreement with FDA. 

Novartis Issues Recall and Suspends Operations at US Facility

GlaxoSmithKline is recalling 394,230 bottles containing its antihypertensive drug DynaCirc CR (isradipine) controlled-release tablets. The lots are being recalled due to concerns regarding the level of cGMP compliance and procedural controls related to line clearance during the packing process at the Lincoln, Nebraska, facility of Novartis Consumer Health, where the product is made.

GlaxoSmithKline Recalls Antihypertensive Drug Made at Novartis Facility

Last week, FDA Commissioner Margaret A. Hamburg 

 before the House Committee on Energy and Commerce, Subcommittee on Health to support the fifth authorization of the Prescription Drug User Fee Act (PDUFA), also known as PDUFA V. She also outlined a series of recommendations, sent to Congress in January 2012, to include in PDUFA V.

The current authorization for PDUFA, PDUFA IV, expires on Sept. 30, 2012, and Hamburg testified that fees collected under PDUFA constitute an important part of the agency’s funding. Of the nearly $932 million obligated in support of the process for the review of human drug applications in fiscal year (FY) 2010, PDUFA fees funded 62% and the rest were through appropriations. Three fees are collected under PDUFA: application fees for new drug applications (NDAs) and biologics license applications (BLAs), product fees, and establishment fees.

In making the case for PDUFA reauthorization, Hamburg highlighted the review performance of FDA. Of the 35 innovative drugs approved in FY 2011, 24, or 70%, were approved by FDA before any other regulatory agency in the world, including the European Medicines Agency. Of 57 novel drugs approved by both FDA and the EU between 2006 and 2010, 43, or 75%, were approved first in the United States. Preliminary data show that in 2011, over half of all new active drug substances were first launched in the US. 


Hamburg also provided a list of recommendations to enhance PDUFA V, which were gained through a series of meetings with the industry, the public, and other stakeholders. These recommendations were sent to Congress on Jan. 13, 2012. These recommendations or “enhancements” to PDUFA V focused on improving communication between FDA and sponsor companies during development, improving regulatory science and innovation at FDA, and expediting drug development.

To increase communication and improve efficiency in the review process, FDA agreed to an enhancement to FDA’s review program for new molecular entity NDAs and original BLAs to include presubmission meetings, mid-cycle communications, and late-cycle meetings between FDA and sponsors for these applications. To accommodate this increased interaction during regulatory review, as agreed to with industry, FDA’s review clock would begin after the 60-day administrative filing review period for this subset of applications.

Five enhancements focus on regulatory science and expediting drug development. These enhancements include:

Establishing drug-development communication and training staff in FDA for improving communication between FDA and sponsors during development

Developing methods for meta analysis in premarket and postmarket clinical evaluations

Improving the agency’s clinical, clinical pharmacology, and statistical capacity to address submissions using biomarkers or pharmacogenomic markers

Improving FDA’s clinical and statistical capacity to address submissions involving patient-reported outcomes and other endpoint-assessment tools, including providing consultation during the early stages of drug development

Facilitating rare disease drug development by FDA issuing relevant guidance, increasing the agency’s outreach efforts to the rare-disease patient community, and providing specialized training in rare-disease drug development for sponsors and FDA staff.

Expanding implementation of FDA’s benefit–risk framework in the drug-review process, including holding public workshops to discuss the application of frameworks for considering benefits and risks that are most appropriate for the regulatory setting.

Standardizing risk evaluation and mitigation strategies (REMS) by initiating a public process to explore strategies and initiate projects to standardize REMS with the goal of reducing burden on practitioners, patients, and others in the healthcare setting. Additionally, FDA will conduct public workshops and develop guidance on methods for assessing the effectiveness of REMS and the impact on patient access and burden on the healthcare system.

Using user-fee funds to conduct a series of activities to determine the feasibility of using the Sentinel (i.e., a national electronic system for FDA to track the safety of drugs, biologics, and medical devices) to evaluate drug-safety issues that may require regulatory action, such as labeling changes, postmarketing requirements, or postmarketing commitments.

Requiring a phased-in requirement for standardized, fully electronic submissions during PDUFA V for all marketing and investigational applications. Through partnership with open-standards development organizations, the agency would also conduct a public process to develop standardized terminology for clinical and nonclinical data submitted in marketing and investigational applications.

The cost of the agreed upon PDUFA V enhancements translates to an overall increase in fees of approximately 6%.

Last week, FDA Commissioner Margaret A. Hamburg testified before the House Committee on Energy and Commerce, Subcommittee on Health to support the fifth authorization of the Prescription Drug User Fee Act, also known as PDUFA V. She also outlined a series of recommendations, sent to Congress in January 2012, to include in PDUFA V.

FDA Commissioner Testifies for PDUFA Reauthorization

 Last week, FDA Commissioner Margaret A. Hamburg testified before the House Committee on Energy and Commerce, Subcommittee on Health to outline the agency’s case for supporting the fifth authorization of the Prescription Drug User Fee Act (PDUFA), also known as PDUFA V. In addition to offering her support for PDUFA V, Hamburg also discussed renewal of legislation for promoting pediatric drug testing, the need of FDA to invest in science and innovation, and the agency’s efforts in confronting the continual challenges of globalization. In tackling globalization, a basic question arises: does the United States face a pharmaceutical manufacturing disconnect?

, Hamburg offered numbers to show the FDA’s record in reviewing applications for new drugs. In fiscal year 2011, FDA approved 35 new drugs, and almost 70% of these drugs were approved by FDA before any other regulatory agency, including the European Medicines Agency. Of 57 novel drugs approved by both FDA and the European Union between 2006 and 2010, 43, or 75%, were approved first in the United States. Preliminary data show that in 2011, over half of all new active drug substances were first launched in the US.

		Although Hamburg offered these numbers to show the agency’s record in approving new drugs, they offer another important insight: namely, the US is an important source and market for drug innovation and pharmaceuticals. The US is the largest national market for pharmaceuticals, accounting for 36%, or $310.6 billion, of the $856 billion global pharmaceutical market in 2010, according to data from the IMS Institute for Healthcare Informatics. The top five EU markets (United Kingdom, France, Germany, Italy, and Spain) accounted for 17%, or $147.4 billion, in 2010. Emerging pharmaceutical markets, which include the BRIC countries (Brazil, Russia, India, and China) and 13 other emerging markets collectively accounted for $150.5 billion, or nearly 18%, of the global pharmaceutical market in 2010, according to IMS.

		The data reveal the attractiveness of the US for launching new drugs and marketing existing drugs, but when it comes to manufacturing drug products or active ingredients, the US falls short. Approximately 40% of the drugs consumed in the US are manufactured outside the US, and up to 80% of the APIs in those drugs come from foreign sources, noted Hamburg in her testimony.

		In her testimony, Hamburg outlined FDA’s efforts to deal with this increased globalization. In July 2011, FDA published a special report, “Pathway to Global Product Safety and Quality,”  a global strategy and action plan for the agency to more effectively oversee the safety of all products that reach US consumers. As detailed in the plan, over the next decade, FDA will focus on strengthened collaboration, improved information- sharing and gathering, data-driven risk analytics, and better allocation of resources through partnerships with counterpart regulatory agencies, other government entities, international organizations, and other key stakeholders, including industry.

		Although these efforts by FDA are important and necessary from a public health and safety perspective, the underlying fundamentals engender a larger public policy question beyond the scope of FDA’s regulatory strategy. In a competitive global economy, what should the US be doing to encourage, cultivate, and retain domestic manufacturing of drug products and APIs? In this election year, debates over how to stimulate economic and employment growth are center stage, but what is noticeably absent is a focused plan to stimulate growth in the bio/pharmaceutical industry, a coveted source of high-technology, science-based innovation. That is one debate that is certainly worth having and one that hopefully will be had.

Last week, FDA Commissioner Margaret A. Hamburg testified before the House Committee on Energy and Commerce, Subcommittee on Health to outline the agency’s case for supporting the fifth authorization of the Prescription Drug User Fee Act (PDUFA), also known as PDUFA V.