Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

As contract manufacturers and fine-chemical producers assemble for CPhI Worldwide, in Madrid, Oct. 9–13, companies are proceeding with expansion of manufacturing capacity, services, and forming new partnerships. Some highlights from 2012 thus far are outlined below. 

has announced a partnership with the Center for Pharmaceutical Engineering Science at the University of Bradford in the United Kingdom. The agreement will enable Bradford scientists to use the GMP capabilities and assets held at Aesica while Aesica will have access to the center’s research facilities. 

 is expanding its UK commercial packaging facility with the acquisition of a Noack N 623 blister packaging line from Romaco. The acquisition comes in response to growing client demand for enhanced flexibility related to larger blister sizes and innovative multi-unit blister formats, coupled to a requirement for nonpermeability and enhanced environmental protection, particularly product humidity control. Earlier this year, Almac increased blister capacity at its US commercial packaging facility in Audubon, Pennsylvania. 

In other news, Almac has launched a new reagent offering based on the provision of homogeneous full-length histones with defined patterns of modification. The histone reagents provide a tool for researchers for drug targets in the field of epigenetics. Almac also expanded its refrigerated storage and labeling facilities at its UK site. 

 entered into an agreement with Knopp Biosciences to provide various discovery-related services that include medicinal chemistry, drug metabolism and pharmacokinetics, and computer-aided drug discovery, as part of AMRI’s Smartsourcing platform. 

 United Drug, a provider of healthcare services, acquired the clinical-services company 

 from Bilcare Limited for a total consideration of $61 million. Bilcare Limited is retaining its clinical supplies business in Asia. 

 is planning an expansion of its large-scale API manufacturing facility in Germantown, Wisconsin. The expansion comes three years after commissioning the new site. The expansion will include additional reactor capacity as well as isolation equipment. Alongside capacity additions, CML has made additional investments in engineering controls to ensure the sustainability of the business. 

 and ADC Biotechnology have agreed to provide customers with development and manufacturing services for antibody drug conjugates. ADC is developing a “lock and release” solid-phase immobilization technology for production of ADCs. The alliance will offer services for the development, scale-up, manufacturing, and formulation of protein-based drug conjugates. ADC Bio will provide access to proprietary solid-phase immobilization technologies for conjugation and long-term storage of ADCs, and Carbogen Amcis will focus on focus on small- to large-scale GMP supply and on the formulation of ADCs. 

 has agreed to supply an API for a customer’s Phase III program. The agreement is expected to contribute more than $20 million in revenues to Cambrex, which will expand its large-scale multipurpose cGMP assets in 2012 and 2013. 

has established a global alliance with Parexel International to help streamline the clinical-trial supply process. The alliance will provide a fully integrated service offering aimed at ensuring the timely and efficient delivery of clinical-trial materials. In other news, Catalent Pharma Solutions and CTC Bio have agreed to provide services to South Korean pharmaceutical companies seeking to commercialize solid oral-dose and controlled-release products in the US and Europe. 

 has expanded the capacity of its Wisconsin-based API manufacturing plant as a result of an increased demand for contract manufacturing of commercial APIs as well as additional upgrades for improving safety and GMP systems. 

has signed a biologics contract manufacturing agreement with Recepta Biopharma, based in Brazil. The contract covers the process development and cGMP manufacture by DSM of one of Recepta’s lead antibodies at DSM’s facilities in Groningen, the Netherlands.

 has invested $2 million to expand its facilities for equipment for product mixing and capsule-filling. Delivery of the new equipment started in August and will be completed by February 2013. 

Haupt Pharma successfully passed inspections by FDA at four sites in Germany during the first half of 2012. 

 agreed to acquire an API manufacturing facility and an associated R&D facility from Orchid Chemicals & Pharmaceuticals, an Indian pharmaceuticals company, for approximately $200 million. The proposed acquisition follows Hospira’s 2010 purchase of Orchid’s generic injectable business and permits Hospira to be vertically integrated into certain beta-lactam antibiotic APIs. 

 has expanded its solutions to solve issues of poor bioavailability, patient acceptability, and delivery for non-oral routes of administration. Hovione’s toolkit of solutions includes crystal design, particle-size reduction to the micro or nano-scale, and amorphous solid dispersions. These services are offered from bench to commercial scale and are complemented with formulation development and clinical manufacture to Phase II. 

 contract manufacturing and services division has launched an analytical services unit that will provide laboratory method development and related analytical testing as part of its integrated service offerings. 

has announced a EUR 3-million ($3.69 million) investment to expand its highly potent API manufacturing capabilities at its Le Mans, France, facility. The expansion is expected to be fully operational by the beginning of 2013.

 and Molecular Profiles have formed an agreement to deliver end-to-end services from initial drug discovery to early- and late-phase manufacturing. 

 sold its global secondary clinical packaging and clinical distribution services business to Bellwyck Packaging Solutions, a provider of clinical-trial and contract services for secondary packaging. 

has received regulatory approval from French health authorities to fill biotechnology products at its site in Monts, France. The Monts site, which employs 200 personnel, comprises three filling lines. Two large capacity lines are used for glass vials for injection and a third one is an aseptic line that fills cartridges. 

, part of Sigma-Aldrich, plans to expand its operations in Scotland by investing in the development of a new powder-manufacturing facility on its Irvine site. SAFC’s new facility in Irvine is its second powder manufacturing facility, which will support SAFC’s risk-management program, providing an internal back-up supplier for its customers. The new facility will be used to service customers across Europe and will create 24 new jobs. The project is being supported by a £1.5-million ($2.42 million) Regional Selective Assistance grant from Scottish Enterprise. 

 has announced that its Tainan, Taiwan, facility will provide commercial manufacturing of topiramate, the API for Vivus’s Qsymia, a new drug for treating obesity that was approved by FDA on July 17, 2012. 

 completed an expansion of its Fairfield, New Jersey, facility on Sept. 20, 2012. The expansion enlarges the size of the facility from 15,000 to 30,000 ft

 by adding modernized and new GMP/GLP-compliant laboratories, and increases ICH Zone 1–4 storage capacities. 

has begun construction of its new compression molding facility in Sri City, India. The plant will become part of West’s global supply chain for its pharmaceutical packaging operations. 

 facility in Tampa, Florida, on Sept. 14, 2012. The building will be used for primary and secondary packaging, labeling, distribution, and warehouse services. This is the company’s second facility in the Tampa Bay area, and the company says it will be audited and approved for domestic as well as European clinical trials. 

Articles

Fine-chemical manufacturers producers and contract manufacturers roll out manufacturing and service expansions at CPhI in Madrid.

Fine-Chemical Producers and Contract Manufacturers Assemble at CPhI

Elucidating the structure and sequence of proteins is an important task in understanding the biological properties of a protein and its potential as a therapeutic target. Producing a well-ordered crystal, particularly for proteins, which can be studied through crystallography, however, is not an easy task. Recent research involves examining the effects of microgravity on protein crystallization and a computational model for protein elucidation.  

Protein crystallization and microgravity effects

The Center for the Advancement of Science in Space (CASIS), manager of the International Space Station (ISS) US National Laboratory, is collaborating with Merck & Co. to conduct research on protein crystallization on board the ISS in 2013. The research will examine the effect on protein crystallization using microgravity. 

In July, CASIS announced its first request for proposals (RFP) focused on advancing protein crystallization using microgravity. Additionally, in early September 2012, CASIS announced an RFP focused on materials testing in the extreme environment of space. Proposals for this RFP will be accepted until Oct. 24,  2012. The final agreement with Merck is dependent on approval by CASIS' evaluation and prioritization process, a requirement for all ISS projects. If approved, the research will begin in mid-2013. 

"We at Merck are excited to work with CASIS and explore the microgravity effects on several bioprocessing applications within the unique environment of the ISS National Lab," said Paul Reichert, chemistry research fellow at Merck Research Laboratories, in a September CASIS press release.  

CASIS is the nonprofit organization promoting and managing research on board the ISS US National Laboratory, which includes a solicitation for proposals in relation to advancing protein crystallization using microgravity. The RFP seeks to identify projects within the field of crystallography that CASIS will support through grant funding, facilitation of service provider partnerships, and flight coordination to and from the ISS. Crystallography is the technique used to determine the three-dimensional structures of protein molecules. Protein crystallization, when performed in space, may produce large, better-organized crystals, thereby allowing for more focused drug development. CASIS believes that its RFP will lead to the production of better crystals in the microgravity environment than can be grown on Earth.  

"CASIS has evaluated research performed to date in the life sciences and believes it is time to formally test the promising hypothesis that microgravity may produce greater internal order in protein-crystal growth," said CASIS acting Chief Scientist Timothy Yeatman, in a June 26, 2012, CASIS press release. "This could potentially lead to sharper resolution of crystals and their cognate proteins, which could produce more effective drugs for cancer and other debilitating human diseases." 

In 2005, the US Congress designated the US portion of the ISS as the nation's newest national laboratory to maximize its use for improving life on Earth, promoting collaboration among diverse users, and advancing science, technology, engineering, and mathematics education. The laboratory environment is available for use by other US government agencies and by academic and private institutions to provide access to the permanent microgravity setting, vantage point in low-earth orbit, and varied environments of space. 

Computational approaches for protein elucidation

Determining the structure and sequence of proteins is an important part of understanding the protein's biological properties and potential utility as a drug. Designing predetermined crystal structures, however, can be subtle given the complexity of proteins and the noncovalent interactions that govern crystallization (1). Researchers at the University of Pennsylvania recently reported on a computational approach for the design or proteins that self-assemble in three dimensions to yield macroscopic crystals (1).  

"People have designed crystals out of smaller, much less complex molecules than proteins, but protein design is much more subtle," said Jeffrey G. Saven, associate professor of chemistry and biological and theoretical physical chemistry at the University of Pennsylvania, in a university press release. Saven conducted the research and recently reported on its results (1). Protein crystals are attractive as a nano-scale building material because their properties, particularly their exterior surfaces, are highly customizable, according to the university release.  

The researchers targeted a crystal built using a relatively small protein containing a sequence of 26 amino acid positions. The researchers assigned specific amino acids to eight of the positions, but with 18 different types of amino acid to choose from for each of the remaining 18 slots, the algorithm addressed well more than 1022 potential combinations. The researchers accounted for other characteristics, such as the spacing between proteins and their orientation with respect to one another, increasing the variables being considered, according to the release.  

"We worked on synthesizing both of those steps, doing the characterization of structure and the sequence at the same time," said Saven said in the university release. "As we move through this process, we eliminate things that will never work, such as proteins where atoms overlap in space or where amino acids don't fit into a given site. At the same time, we identify proteins that, as you vary the structure, are likely to yield a crystal." 

Specifically, the research used a three-helix coiled-coil protein designed 

 to form a polar, layered, three-dimensional crystal having the P6 space group, which had a "honeycomb-like" structure and hexameric channels that spanned the crystal (1). The approach involved creating an ensemble of crystalline structures consistent with the targeted symmetry, characterizing this ensemble to identify "designable" structures from minima in the sequence–structure energy landscape and designing sequences for these structures, and experimentally characterizing candidate proteins. This approach to crystal design has potential applications to the 

 design of nanostructured materials and to the modification of natural proteins to facilitate X-ray crystallographic analysis.  

The target crystal the researchers produced is a proof of concept. "There's still much we don't know about the interactions that govern crystallization," Saven said, in the university release. "With this technique, we can explore what those interactions are or how we might take an existing protein and engineer those interactions so we get much better structures." 

Recent research on elucidating the structure and sequence of proteins involves examining the effect of microgravity on protein crystallization and a computational model for protein elucidation.

Advancing Protein Crystallization: Microgravity Effects and Predictive Models

The physical form of an API is important in formulation development for resolving issues in bioavailability and solubility. Particle-engineering technologies can be applied in various ways: crystal design for controlling crystallization and producing cocrystals; particle-size reduction, achieved through jet-milling, wet polishing and nanoparticle generation; and amorphous solid dispersions, produced by several approaches, such as spray-drying (including as inclusion complexes), hot-melt extrusion (HME), and spray-congealing. 

discussed these issues with Colin Minchom, vice president, of the Particle Design Business Unit at Hovione.  

 Under what type of situations would crystallization be used? How does it facilitate the delivery of poorly soluble drugs?  

 Interest in cocrystals has increased in recent years, and the recent FDA guidance on a proposed classification of cocrystals has prompted further discussion and counter proposals from the industry. The proposed US FDA classification of cocrystals as crystalline materials containing two or more molecules in the same crystal lattice is limited but can serve as a starting point for discussion.  

The addition of a cocrystal former into the crystalline structure of the API changes its physical and chemical properties. It is possible, in some cases, to improve bioavailability to adequate levels while preserving the stability of a crystalline form. For APIs with low glass-transition temperatures, a cocrystal may be favoured over the amorphous form. As such, the use of a cocrystal may be an attractive platform to overcome the solubility limitations of Biopharmaceutics Classification System Class II and Class IV drugs.  

Cocrystal formation is a favored approach for increasing apparent aqueous solubility for poorly water-soluble molecules that have no ionizable groups, and for which salt formation is not possible, or for where the physical properties of the salts formed are not desirable. Solvates and hydrates are well-accepted crystal forms. In many ways, a cocrystal can be thought of as a solvate, but one whose components are solid at room temperature. The cocrystal will form if the resulting crystal is thermodynamically more stable than the components. Resulting cocrystal properties are dependent upon many factors, including the starting properties of the API, the physical properties of the co-former and the mechanism by which the cocrystal is formed. To increase the probability of success, we [Hovione] recommend that at early-development stages to test other proven platforms, such as solid dispersions, micronized and nanosized crystals and inclusion complexes.  

Applying acoustic levitation for elucidation of amorphous material  

 Controlling nucleation during crystallization is an important task. What are the mechanisms for controlling crystallization?  

 Where milling techniques can be thought of as top-down sizing techniques, controlled crystallization is where the desired particle-size distribution is achieved from the bottom up. The objectives of a crystallization process are twofold. On the one hand, the aim is to isolate the API in the right crystal form, typically a polymorph that provides the required level of exposure and stability. On the other hand, crystallization may also be a purification stage, whereby the impurities remain mostly dissolved in the mother liquors.  

The kinetics of crystallization (nucleation and crystal growth rates) are driven by the imposed supersaturation levels. The degree of supersaturation, temperature ramp, mixing, filtration and final drying process all contribute to the final particle-size distribution. Moreover, the relative importance of each factor can change at each scale.  

What factors determine particle size? What are the differences in particle size achieved through jet-milling, wet polishing, and nanoparticle generation?  

 Particle-size reduction is not a simple phenomenon. The mechanism of generating the material of the prescribed particle size has a profound effect upon a range of physical properties that may have a significant effect on the resulting pharmaceutical behavior. The final particle size of a material subjected to a comminution process is dictated by particle attributes, such as crystal hardness, morphology, and original crystal size, as well as the size-reduction method and energy applied. Jet-milling and wet polishing may generate materials with equivalent median particle sizes; however, the resulting span from jet-milled material is likely to be wider than the wet-polished material. Amorphous material and highly reactive surfaces also may result from jet-milling while a higher level of crystallinity is maintained with wet polishing. 

Dry methods, such as jet-milling, tend to be more cost-effective (mainly because they do not require sophisticated isolating techniques), but they are more aggressive, less reproducible, and more limited in terms of the achievable size reduction.  

 What factors determine which method (i.e., spray-drying, HME, spray-congealing, and inclusion-complex generation) to use to produce the amorphous solid dispersion?  

 Amorphous solid dispersions represent a tremendous opportunity for solubility enhancement of oral drugs. The resulting supersaturation levels (and hence bioavailability) and the physical stability of the final dosage form, however, depend on the manufacturing method applied. Many approaches are available to generate amorphous solid dispersions.   

Spray-drying, being a solvent method, is the most versatile technique to obtain solid dispersions due to its gentle process conditions and much wider formulation options. Spray-drying is a technology that works well in nearly every compound. Another advantage of spray-drying is that it can be effectively operated using much smaller quantities of drug substance, thereby making it the most cost-effective option during early-stage development. 

Melt methods, such as HME and spray-congealing, on the other hand, are more cost effective at the larger scale manufacturing and have the additional advantage of being solvent-free techniques. To use these methods, however, the compound needs to be soluble in the polymer/matrix and physically stable complexes need to be created. These methods are also limited to drug substances that can sustain relatively high heat loads. All these techniques are relatively well-established within the pharmaceutical industry, although spray-drying is a step ahead in terms of maturity.  

Although challenging at a very small scale, the rationale design of an HME formulation is viable when the API is available in pilot-scale quantities. Where an API has low solubility in all preferred spray-drying solvents or retains extensive solvent following drying, HME may represent the best way forward for the development of a stable amorphous solid dispersion. Spray-congealing can uses a number of lipophilic excipients, which are useful in formulating poorly water-soluble compounds that will form self emulsifying drug-delivery systems (SEDD) or self micro-emulsifying drug-delivery systems (SMEDDS) on administration, as well as the polymers commonly used in spray-dried amorphous solid dispersions. 

 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072,  

Particle-engineering technologies, such as crystal design for crystallization and producting cocrystals, particle-size reduction, and amorphous solid dispersions, help to optimize delivery of a drug.

Seeking Solutions in Solid-State Chemistry

As pharmaceutical companies face  shortfalls in R&D productivity and  increased generic-drug incursion, product lifecycle management becomes increasingly important. Combination therapies provide an opportunity for innovator drug companies to extend the lifecycle of a given API by developing a fixed-dose combination product that may offer improved and synergistic efficacy, improved dosing regimes, and greater patient compliance. Combination drugs also allow specialty pharmaceutical companies to use specialized drug-delivery and formulation strategies for product differentiation. Challenges, however, exist in developing fixed-dose combination products compared with single API products, such as maintaining the physical and chemical stability of the APIs and modulating drug release. 

Combination products encompass a wide range of products, including drug–device combinations. By regulatory definition, a 

 is a product composed of any combination of a drug and a device; a biological product and a device; a drug and a biological product; or a drug, device, and a biological product (1, 2). Under 21 

 3.2 (e), a combination product is defined to include: 					

"A product comprised of two or more regulated components (i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic) that are physically, chemically, or otherwise combined or mixed and produced as a single entity" (e.g., a monoclonal antibody combined with a therapeutic drug, a device coated or impregnated with a drug or biologic, prefilled syringes, insulin injector pens, metered dose inhalers, and transdermal patches). 

"Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products" (e.g., drug or biological product packaged with a delivery device). 

A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and…the labeling of the approved product would need to be changed (e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose)."  

"Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect" (e.g., photosensitizing drugs and activating laser/light sources and iontophoretic drug delivery patches and controllers) (1–3).  

In fiscal year 2011, FDA received 288 original applications classified into nine categories of combination products (see 

). These applications included 26 new drug applications and 134 new investigational new drug applications, of which the majority were drug–device combinations (see 

Table I: Number and type of combination drug products for original applications for new drug applications (NDAs), biologics license applications (BLAs), premarket approval applications (PMAs), premarket notifications (510(k)s, investigational new drugs (INDs), investigational device exemptions (IDEs), and humanitarian-use exemptions (HDEs) received in fiscal year 2011 by FDA.			

Combination products also include oral fixed-dose combination drugs of two or more APIs in a single product form (i.e., tablet and capsule). According to 21 

 300.50, "two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug" (4). 

Several high-profile solid-dosage fixed-combination therapies recently entered the US market (see 

) with several large pharmaceutical companies either partnering on or singularly launching combination drugs (5). Earlier in 2012, Boehringer Ingelheim and Eli Lilly received FDA approved for Jentadueto (linagliptin and metformin hydrochloride [HCl]) for treating Type II diabetes. In January 2011, Boehringer Ingelheim and Eli Lilly formed a strategic alliance in diabetes, and Boehringer Ingelheim partnered with the CDMO Patheon, in a three-year deal announced in October 2011, for developing fixed-dose combination drugs to treat Type II diabetes. As part of their diabetes alliance, AstraZeneca and Bristol-Myers Squibb developed Kombiglyze XR (saxagliptin HCl and metformin HCl), which was approved in 2010. In August 2012, the companies expanded their alliance following Bristol-Myers Squibb's acquisition of Amylin Pharmaceuticals. Merck & Co. received approval earlier this year for Janumet XR, an extended-release formulation of its fixed-dose combination of sitagliptin phosphate and metformin HCl (see 

Table II: Examples of FDA approvals of solid-dosage combination drugs, 2010â2012 (Ref. 5) (Contin. on page 47).			

Gilead Sciences received FDA approval for two oral fixed-dose antiviral combination products—Complera (emtricitabine, rilpivirine HCl, tenofovir disoproxil fumurate) in 2011 and Stribild (elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumurate) in 2012—and received a new indication of treating HIV infection in 2010 with Truvada (emtricitabine and tenofovir disoproxil fumurate). Novartis developed two fixed-dose combination products using aliskiren hemifurmate, the API in its antihypertensive drug Tekturna. In 2010, Novartis received FDA approval for Amturnide (aliskiren hemifurmate, amlodipine besylate, and hydrochlorothiazide) and for Tekamlo (aliskiren hemifumarate and amlodipine besylate). Daiichi Sanyko also used amlodipine with one of its APIs (olmesartan) for the combination product, Tribenzor (olmesartan medoxil, amlodipine besylate, and hydrochlorothiazide), which FDA approved in 2010. Bayer gained approval for several oral contraceptive fixed-dose combinations (see 

Fixed-dose combination therapies are a challenge. The presence of an additional API or APIs adds complexity to the formulation in maintaining the physical and chemical stability of the APIs, mitigating interactions (i.e., API–API, API–excipient, excipient–excipient), reconciling incompatible pharmacokinetics, and addressing differing drug-release rates and targets in drug delivery. Some ways to address these problems in solid-dosage fixed dose combinations include monolayer tablets, bilayer tablets, trilayer tablets, inlay tables, and pellets or granules in capsules (6). 

Nano-syringes for delivering combination-drug therapies			

Recently approved fixed-dose combination products use various strategies. Merck & Co.'s Janumet XR is an extended-release metformin core tablet coated with an immediate-release layer of sitagliptin. The sitagliptin layer is coated with a soluble polymeric film (7). Merck's Juvisync is a bilayer tablet containing sitagliptin phosphate and simvastatin (8). Vivus's Qsymia is a capsule consisting of immediate-release phentermine HCL and extended-release topiramate (9). GlaxoSmithKline's Jalyn consists of one dutasteride soft-gelatin capsule, dissolved in a mixture of butylated hydroxytoluene and mono-diglycerides of caprylic/capric acid, and pellets of tamsulosin HCl with excipients of methacrylic acid copolymer dispersion, microcrystalline cellulose, talc, and triethyl citrate, encapsulated in a hard-shell capsule (10). Reckitt's  Suboxone is a sublingual film (11).  

Tablets are the main product form for fixed-dose combinations, but other technologies can be used. For example, Procaps, which recently partnered with Patheon in softgel development and manufacturing services, offers its Unigel technology, which provides various forms for fixed-dose combinations, such as a softgel in a softgel, a tablet in a softgel, granules in a softgel, or any combination to address challenges of multiactive formulation (6). The Indian drug manufacturer Cipla is partnering with the Drugs for Neglected Diseases initiative (DNDi) to develop a four-in-one fixed-dose combination antiviral therapy using a "sprinkle" formulation of lopinavir and ritonavir, combined with one of two other antiviral APIs, abacavir/lamivudine or zidovudine/lamivudine. Cipla is developing a sachet product in which the four antiviral drugs will be in tastemasked and put in granular form for mixing into food or liquids with the aim of registering the drug by 2015, according to a July 20, 2012, DNDi press release. 

, Title 21, Food and Drugs (Government Printing Office, Washington, DC), Chapter I, Part 3, Subchapter A, Sec. 3.2 (e).  

FY 2011 Performance Report to Congress for the Office of Combination Products

 3. FDA, "Frequently Asked Questions About Combination Products" (Rockville, MD), 

www.fda.gov/CombinationProducts/AboutCombinationProducts/ucm101496.htm

, Title 21, Food and Drugs (Government Printing Office, Washington, DC) Chapter 1, Part 300, Subpart B, Sec. 300.50.  

 6. A. Kane, D. Monterroza, and C. Salazar, "Unlocking the Power of New Softgel Technology for Multiple Formulations" Webcast, 

Fixed-dose combination drug therapies give rise to innovation in solid-dosage formulations and manufacturing.

Combination Drugs: Adding Up the Opportunities

The physical form of an API is important in formulation development for resolving issues in bioavailability and solubility. Particle-engineering technologies can be applied in various ways: crystal design for controlling crystallisation and producing cocrystals; particle-size reduction, achieved through jet-milling, wet polishing and nanoparticle generation; and amorphous solid dispersions, produced by several approaches, such as spray-drying, hot-melt extrusion (HME), spray-congealing and inclusion-complex generation. 

 discussed these issues with Colin Minchom, vice president, Particle Design Business Unit, at Hovione.  

: Under what type of situations would cocrystallisation be used? How does it facilitate the delivery of poorly soluble drugs?  

The addition of a cocrystal former into the crystalline structure of the API changes its physical and chemical properties. It is possible, in some cases, to improve bioavailability to adequate levels while preserving the stability of a crystalline form. For APIs with low glass-transition temperatures, a cocrystal may be favoured over the amorphous form. As such, the use of a cocrystal may be an attractive platform to overcome the solubility limitations of Biopharmaceutics Classification System Class II and Class IV drugs. Cocrystal formation is a favoured approach for increasing apparent aqueous solubility for poorly water-soluble molecules that have no ionisable groups, and for which salt formation is not possible, or for where the physical properties of the salts formed are not desirable.  

Solvates and hydrates are well-accepted crystal forms. In many ways, a cocrystal can be thought of as a solvate, but one whose components are solid at room temperature. The cocrystal will form if the resulting crystal is thermodynamically more stable than the components. Resulting cocrystal properties are dependent upon many factors, including the starting properties of the API, the physical properties of the co-former and the mechanism by which the cocrystal is formed.  

To increase the probability of success, we [Hovione] recommend that at early-development stages to test other proven platforms, such as solid dispersions, micronised and nanosized crystals and inclusion complexes.  

: Controlling nucleation during crystallisation is an important task. What are the mechanisms for controlling crystallisation?  

 Where milling techniques can be thought of as top-down sizing techniques, controlled crystallisation is where the desired particle-size distribution is achieved from the bottom up. The objectives of a crystallisation process are twofold. On the one hand, the aim is to isolate the API in the right crystal form, typically a polymorph that provides the required level of exposure and stability. On the other hand, crystallisation may also be a purification stage, whereby the impurities remain mostly dissolved in the mother liquors.  

The kinetics of crystallisation (nucleation and crystal growth rates) are driven by the imposed supersaturation levels. The degree of supersaturation, temperature ramp, mixing, filtration and final drying process all contribute to the final particle-size distribution. Moreover, the relative importance of each factor can change at each scale.  

 What factors determine particle size? What are the differences in particle size achieved through jet-milling, wet polishing, and nanoparticle generation?  

 Particle-size reduction is not a simple phenomenon. The mechanism of generating the material of the prescribed particle size has a profound effect upon a range of physical properties that may have a significant effect on the resulting pharmaceutical behaviour. The final particle size of a material subjected to a comminution process is dictated by particle attributes, such as crystal hardness, morphology and original crystal size, as well as the size-reduction method and energy applied. Jet-milling and wet polishing may generate materials with equivalent median particle sizes; however, the resulting span from jet-milled material is likely to be wider than the wet-polished material. Amorphous material and highly reactive surfaces also may result from jet-milling while a higher level of crystallinity is maintained with wet polishing.  

Dry methods, such as jet-milling, tend to be more cost-effective (mainly because they do not require sophisticated isolating techniques), but they are more aggressive, less reproducible and more limited in terms of the achievable size reduction.  

 What factors determine which method (i.e., spray-drying, HME, spray-congealing and inclusion-complexation generation) to use to produce the amorphous solid dispersion?  

While challenging at a very small scale, the rationale design of an HME formulation is viable when the API is available in pilot-scale quantities. Where an API has low solubility in all preferred spray-drying solvents or retains extensive solvent following drying, HME may represent the best way forward for the development of a stable amorphous solid dispersion. Spray-congealing can uses a number of lipophilic excipients, which are useful in formulating poorly water-soluble compounds that will form self emulsifying drug-delivery system (SEDD) or self micro-emulsifying drug-delivery systems (SMEDDS) on administration, as well as the polymers commonly used in spray-dried amorphous solid dispersions. 

Applying acoustic levitation for elucidation of amorphous material. 

Researchers at the US Department of Energy's Argonne National Laboratory have discovered a way to use sound waves to levitate individual droplets of solutions containing pharmaceuticals (1). The research facilitates the process for placing drugs from solution into an amorphous state.  

The researchers applied an acoustic levitator that uses two small speakers to generate sound waves at frequencies slightly above the audible range at approximately 22 kilohertz (1). With the proper alignment of the top and bottom speakers, the speakers create two sets of sound waves that produce a standing wave. At certain points along the standing wave, there is no net transfer of energy. The acoustic pressure from the sound waves is sufficient to overcome the effect of gravity, thereby allowing light objects to levitate when placed at these points in the standing wave (1). A video showing the technology may be found at the laboratory's website (

The technology now can produce only small quantities in an amorphous state, but it is considered a useful tool in elucidating the conditions that optimise producing amorphous material.  

Argonne National Laboratory's Technology Development & Commercialization Division is developing a patent for the method and is evaluating the technology for licensing for commercial development with pharmaceutical industry partners (1). 

Chris Benmore, an X-ray physicist at Argonne National Laboratory, led the study and teamed with various scientists for adapting the technology for drug research. These scientists include Professors Stephen Byrn and Lynne Taylor in the Department of Industrial and Physical Pharmacy in the College of Pharmacy at Purdue University (US) and Professor Jeffrey Yarger of the Department of Chemistry and Biochemistry at Arizona State University (US) and director of the university's Magnetic Resonance Research Centre. The researchers also are now working on identifying drugs most suited to applications with the acoustic levitator.  

1. J. Sagoff,  "Real-world Levitation to Inspire Better Pharmaceuticals" (Argonne National Laboratory Information, Argonne, IL [US[), Sept. 12, 2012.  

Advancing protein crystallisation: microgravity effects and predictive models. 

Elucidating the structure and sequence of proteins is an important task in understanding the biological properties of a protein and its potential as a therapeutic target. Producing a well-ordered crystal, particularly for proteins, which can be studied through crystallography, however, is not an easy task. Recent research involves examining the effects of microgravity on protein crystallisation and a computational model for protein elucidation.  

Protein crystallisation and microgravity effects

The Centre for the Advancement of Science in Space (CASIS), manager of the International Space Station (ISS) US National Laboratory, is collaborating with Merck & Co. to conduct research on protein crystallisation on board the ISS in 2013. The research will examine the effect on protein crystallisation using microgravity. 

In July, CASIS announced its first request for proposals (RFP) focused on advancing protein crystallisation using microgravity. Additionally, in early September 2012, CASIS announced an RFP focused on materials testing in the extreme environment of space. Proposals for this RFP will be accepted until 24 Oct. 2012. The final agreement with Merck is dependent on approval by CASIS' evaluation and prioritisation process, a requirement for all ISS projects. If approved, the research will begin in mid-2013. 

CASIS is the nonprofit organisation promoting and managing research on board the ISS US National Laboratory, which includes a solicitation for proposals in relation to advancing protein crystallisation using microgravity. The RFP seeks to identify projects within the field of crystallography that CASIS will support through grant funding, facilitation of service provider partnerships, and flight coordination to and from the ISS. Crystallography is the technique used to determine three-dimensional structures of protein molecules. Protein crystallisation, when performed in space, may produce large, better-organised crystals, thereby allowing for more focused drug development. CASIS believes that its RFP will lead to the production of better crystals in the microgravity environment than can be grown on Earth.  

"CASIS has evaluated research performed to date in the life sciences and believes it is time to formally test the promising hypothesis that microgravity may produce greater internal order in protein-crystal growth," said CASIS acting Chief Scientist Timothy Yeatman, in a 26-June 2012, CASIS press release. "This could potentially lead to sharper resolution of crystals and their cognate proteins, which could produce more effective drugs for cancer and other debilitating human diseases." 

In 2005, the US Congress designated the US portion of the ISS as the nation's newest national laboratory to maximise its use for improving life on Earth, promoting collaboration among diverse users, and advancing science, technology, engineering and mathematics education. The laboratory environment is available for use by other US government agencies and by academic and private institutions to provide access to the permanent microgravity setting, vantage point in low-earth orbit and varied environments of space. 

Determining the structure and sequence of proteins is an important part of understanding the protein's biological properties and potential utility as a drug. Designing predetermined crystal structures, however, can be subtle given the complexity of proteins and the noncovalent interactions that govern crystallisation (1). Researchers at the University of Pennsylvania recently reported on a computational approach for the design or proteins that self-assemble in three dimensions to yield macroscopic crystals (1).  

"People have designed crystals out of smaller, much less complex molecules than proteins, but protein design is much more subtle," said Jeffrey G Saven, associate professor of chemistry and biological and theoretical physical chemistry at the University of Pennsylvania, in a university press release. Saven conducted the research and recently reported on its results (1). Protein crystals are attractive as a nano-scale building material because their properties, particularly their exterior surfaces, are highly customisable, according to the university release.  

The researchers targeted a crystal built using a relatively small protein containing a sequence of 26 amino acid positions. The researchers assigned specific amino acids to eight of the positions, but with 18 different types of amino acid to choose from for each of the remaining 18 slots, the algorithm addressed well more than 10

  potential combinations. The researchers accounted for other characteristics, such as the spacing between proteins and their orientation with respect to one another, increasing the variables being considered, according to the release.  

"We worked on synthesising both of those steps, doing the characterisation of structure and the sequence at the same time," said Saven said in the university release. "As we move through this process, we eliminate things that will never work, such as proteins where atoms overlap in space or where amino acids don't fit into a given site. At the same time, we identify proteins that, as you vary the structure, are likely to yield a crystal." 

 to form a polar, layered, three-dimensional crystal having the P6 space group, which had a "honeycomb-like" structure and hexameric channels that spanned the crystal (1). The approach involved creating an ensemble of crystalline structures consistent with the targeted symmetry, characterising this ensemble to identify "designable" structures from minima in the sequence–structure energy landscape and designing sequences for these structures, and experimentally characterising candidate proteins. This approach to crystal design has potential applications to the 

The target crystal the researchers produced is a proof of concept. "There's still much we don't know about the interactions that govern crystallisation," Saven said, in the university release. "With this technique, we can explore what those interactions are or how we might take an existing protein and engineer those interactions so we get much better structures." 

The physical form of an API is an important consideration in formulation development. Particle-engineering technologies, such as crystal design for controlling crystallisation and producing cocrystals, particle-size reduction and amorphous solid dispersions, help to optimise delivery of a drug.

Watson Laboratories, a subsidiary of Watson Pharmaceuticals, issued a voluntary recall in the US for two lots of hydrocodone bitartrate and acetaminophen tablets, USP 10 mg/500 mg. Watson issued the recall on Sept. 21, 2012, and has informed FDA of the recall. 

The voluntary recall followed a customer complaint that tablets were thicker and a darker shade than the other tablets. The recall included hydrocodone bitartrate and acetaminophen tablets, USP 10 mg/500 mg, 500 count NDC 00591-0540-05, lot numbers 519406A and 521759A, both with the expiry date April 2014. In a Sept. 21, 2012, 

, Watson says it is possible that some tablets from lots 519406A and 521759A exceed the weight specification and may contain higher than indicated amounts of the ingredients hydrocodone bitartrate and/or acetaminophen. Hydrocodone bitartrate and acetaminophen tablets are approximately 0.6 inches in length, blue, bisected capsule shaped, with "Watson 540" debossed on one side of the tablet. 

The product, hydrocodone bitartrate and acetaminophen 10 mg/500 mg tablets, are indicated for the relief of moderate to moderately severe pain. The affected lots were distributed between June 27, 2012 and July 18, 2012 to wholesale distributors and retail pharmacies nationwide. The lot numbers can be found on the manufacturer's bottle label.

The company says that unintentional ingestion of excessive amounts of acetaminophen may potentially result in an adverse event, including liver toxicity, especially in patients on other acetaminophen-containing medications, patients with liver dysfunction, or people who consume more than three alcoholic beverages a day. The product label warns consumers that acetaminophen overdose can potentially cause severe liver damage, at times resulting in liver transplant or death. Unintentional ingestion of excessive amounts of  hydrocodone may result in an adverse event, including an increase in the severity or frequency of side effects, such as sedation or respiratory depression, particularly in patients who are elderly, have severe kidney or liver impairment, or are also taking interacting medications, for example other sedating medications or certain antidepressants.  No reports of injuries related to the recalled product have been received to date, according to the company. 

Watson Laboratories has recalled two lots of hydrocodone bitartrate and acetaminophen tablets.