Finding Solutions - Fármacos pouco solúveis

SPRAY DRYING GEA Niro’s Pharma Test Station, in Copenhagen, offers contract services.

When they get together, pharmaceutical researchers call drug compounds by nicknames such as “brick dust” and “grease.” Whether compounds are crystalline rocks, lipophilic goo, or something in between, getting them to be water soluble can be a major hurdle for making therapies bioavailable in the body. If the bioavailability is low, meaning only a fraction of a dose gets into circulation, even the best molecule can fail as a drug.

About 40% of marketed drugs are thought to be poorly water soluble. Development efforts might have to be redoubled, however, because between 70 and 90% of drug candidates in the pipeline are believed to have low solubility. In fact, solving solubility problems is considered to be the leading challenge in drug development.

The blame for all these undesirable compounds can be placed on the modern drug discovery process. Drug development scientists point out that combinatorial chemistry and high-throughput screening methods have selected compounds on the basis of their specificity and binding affinity for biological targets. As a result, drug candidates have shifted toward higher molecular weights and greater lipophilicities.

“It’s extraordinarily exciting to find a drug that binds very well with what you think absolutely is the target site that will affect disease, and it’s awfully tough when someone says, ‘It’s a nice molecule, but we are never going to be able to make a product out of it,’ ” says Robin H. Bogner, associate professor of pharmaceutics at the University of Connecticut (UConn). She is also a faculty member at the Center for Pharmaceutical Processing Research (CPPR), which was created as a National Science Foundation university-industry program.

Solubility isn’t the whole picture in bioavailability, but it’s a big part of it, Bogner explains. An oral drug must first dissolve to achieve a level of solubility in the blood. Permeability of the drug in the body is also important, as are food interactions, metabolic differences, disease conditions, and degradation effects. With high bioavailability, any variability in efficacy among patients or for one patient at different times will be minimized, Bogner says.

To highlight the important physical properties of drugs, the Food & Drug Administration uses a Biopharmaceutics Classification System (BCS) with four categories based on solubility and permeability. About 35% of marketed drugs, but only 5–10% of drug candidates, fall into Class I, the “sweet spot” of high solubility and high permeability. At the other extreme, Class IV, with its low solubility and low permeability, has about 10% of marketed drugs and 10–20% of those in development.

It would be nice if all drug candidates were Class I; in fact, FDA waives certain clinical- and product-release testing by manufacturers for some drugs in this class. Still, most candidates fall into Class II, which isn’t all bad news. Although these drugs might have low solubility, they are at least highly permeable. Industry researchers say solubility problems are easier to overcome than permeability issues, and no one wants to have to solve both.

What drug developers want is a physical drug form that has the best properties. Crystalline forms are the most stable, which is good for a drug that will sit on the shelf. But in practice they tend to be the least soluble—if they are not salts—because it takes more energy to overcome intermolecular forces in the crystal lattice and release the molecules into solution. Amorphous states, where the molecules are not so rigidly arranged, fall apart more easily.

Even though most drug candidates fall short of having optimal properties, pharma companies aren’t backing away from their troublesome compounds. Instead, they are relying on drug formulation and delivery to make things work. Third-party suppliers with specialized technologies are trying to meet this need.

The pharmaceutical industry has a reputation of being extremely cautious about changes in manufacturing. “If you didn’t have to go some nontraditional route—it didn’t even have to be an exotic one—you just didn’t,” Bogner explains about attitudes in the past. Faced with significant drug solubility problems, however, many drug firms are looking seriously at two approaches that were once nontraditional: hot-melt extrusion and spray drying.

Between 70 and 90% of drug candidates in the pipeline are believed to have low solubility.These methods are of interest to researchers because they can stabilize amorphous drugs as solid dispersions. In the past, the amorphous form was avoided or viewed as a last resort because of its thermodynamic instability and tendency to crystallize into a more stable, insoluble form. With melt extrusion and spray drying, a compound dispersed or dissolved in a drug-grade polymer can be kept amorphous and prevented from crystallizing.

“If you can make a drug amorphous and keep it amorphous during manufacturing, storage, and much of the administration, you can get enormous enhancements in solubility,” says Michael J. Pikal, a CPPR director and a UConn pharmaceutics professor. “If solubility is the limiting factor, you can get a significant enhancement in bioavailability as well.”

The trick to maintaining solubility is preventing crystallization at any stage, including in the body. In the presence of just the tiniest seed crystal, “precipitation occurs rather rapidly, and the game is over,” Bogner says. Precipitation inhibitors and solubilization aids can be added to a dispersion to prevent these crystallite triggers from forming.

Kinetic and thermodynamic factors are at play with regard to the solubility of the drug in the polymer and whether the molecules have enough mobility to nucleate crystal growth. With the increase in the science’s quality and the amount of knowledge amassed, technology providers believe they have a handle on these issues. No longer relying on empiricism, they can apply predictive means to reliably manufacture solid dispersions and ensure their stability and performance.

A few commercial products, notably Abbott Laboratories’ HIV drug combination Kaletra, are convincing pharma firms of the benefits of using solid dispersions. Containing BCS Class II and IV compounds, Kaletra was originally formulated as a liquid-filled capsule. Although it worked as a drug product, it required multiple doses per day, had gastrointestinal side effects, and needed refrigeration.

In 2005, Abbott launched an easier-to-use tablet form created by Soliqs, its drug delivery business unit in Germany. Soliqs began as a collaboration between BASF and Knoll Pharmaceuticals, a former BASF unit that Abbott acquired in 2001, to develop a melt extrusion technology now called Meltrex. Today, Soliqs also works with outside customers, offering nanoparticle and other delivery technologies.

Similarly, in 2002, the Danish drug company H. Lundbeck spun off LifeCycle Pharma on the basis of Meltdose technology. In the Meltdose approach, a drug is incorporated into a meltable polymer. It is then sprayed with fluid-bed equipment onto particle carriers where it dries as a solid dispersion. The particles can be compressed into tablets or made into other dosage forms.

Meanwhile, BASF provides water-soluble polymers and drug solubilizers that help hold drugs in aqueous solution. In late 2009, the company launched Soluplus, which acts as a matrix polymer and solubilizer. Designed for hot-melt extrusion but applicable to spray drying as well, it’s a graft copolymer consisting of polyvinyl caprolactam, polyvinyl acetate, and polyethylene glycol moieties.

Although relatively new to drug production, melt extrusion has been used for decades by the plastics and food industries. The process works by uniformly mixing and heating materials and then pushing the melt through an opening or die. It consolidates what would otherwise be separate steps to make uniform dispersions reproducibly under precise controls.

For oral drugs, the active pharmaceutical ingredient (API) is mixed with a polymer and other excipients, or formulation aids, and then extruded. The product can be shaped directly into tablets or produced as granules and other forms that can be made into solid dosages. Melt extrusion has been used for several years to make drug films, implants, and devices such as contraceptives.

Extrusion is a versatile technology and has many advantages, explains Firouz Asgarzadeh, principal scientist in Evonik Industries’ pharma polymers division. “Not only does it not require any solvent, but it also combines blending, granulation, and shaping of the product in one single continuous step,” he says. It is more cost-effective and leads to greater product consistency compared with carrying out these steps on a batch basis.

Evonik makes anionic, cationic, and neutral methacrylic-based copolymers under the name Eudragit. Because they are ionizable, the polymers are compatible with different compounds and can be tailored to release a drug, depending on the pH, at targeted locations in the intestinal tract. Strong hydrogen bonding also helps with stabilization and drug solubilization.

Solubility Solutions

Formulation Routes To Improve Solubility
If there is something ionizable on a molecule, a chemist can try converting it to a salt form with a good balance between solubility and handling, explains University of Connecticut pharmaceutics professor Michael J. Pikal, who is also a director of the Center for Pharmaceutical Processing Research. Although salt forms have been used for decades, they might not be an option for the high-molecular-weight lipophilic drug candidates around today.

Making a cocrystal and varying the composition and structure of a drug’s solid form by adding a second component can also improve solubility, Pikal points out. Although some cocrystal drugs are in development, he’s not aware of any that have been approved.

Adjusting the physical size through particle manipulation or engineering can help as well. Grinding to micronize a drug or making nanocrystals of it increases the surface area. Such small particles will likely dissolve better and might result in improved solubility, Pikal adds. Drug molecules can also be absorbed onto nanoparticles and other carriers or complexed with materials such as cyclodextrins.

Stabilizing the amorphous state in a polymer matrix is another option. Liquid and lipid-based formulations using oils, emulsifiers, and surfactants can be encapsulated for delivery. In this area, self-emulsifying and self-microemulsifying drug delivery systems that can help solubilize materials are gaining ground.
The company has developed a Melt Extrusion Modeling & Formulation Information System, or MEMFIS, to select the appropriate polymers, plasticizers, and processing conditions for a given API. To make a determination, MEMFIS uses chemical structures, solubility parameters, physicochemical properties, and more than 1,300 in-house trial processing conditions, Asgarzadeh says.

In less than a week’s time, MEMFIS can generate material and process parameters that will lead to enhanced solubility. “We are able to minimize the number of experiments our customers need to do in order to come up with a viable formulation,” Asgarzadeh says. The system also works with polymers other than Evonik’s.

Having invested for more than a decade, the company has melt extruders at its technical centers in India, Germany, and the U.S. Small-scale production under current Good Manufacturing Practices (cGMP) conditions is available in Darmstadt, Germany. Through an alliance with solid-dosage contract manufacturer Rottendorf Pharma, Evonik can transfer customer projects to that firm’s facilities to make larger quantities.

Evonik has customer projects in all stages of development, Asgarzadeh says. Although only a few marketed oral products use the technology, “I feel the momentum,” he says. “And within the next two to three years, I believe we will see a lot more being approved.” With conventional technologies, he adds, “many of these compounds could not have been formulated into acceptable dosage forms.”

More so than in the past, drug firms are addressing solubility issues early in development, according to contract manufacturers. “You want the drug to be as effective as possible and to have the lowest dose for compliance and cost reasons,” says Timothy G. Bee, senior director for pharmaceuticals at International Specialty Products. “The more effective your formulation, the fewer problems you are going to run into and the more consistent your product is going to be.”

As drug companies become familiar with new dispersion technologies, “they will go right to one that will give them the best chance of success,” Bee says. They should be able to move molecules forward faster by spending less time fishing for something that works or by shifting gears in development. Some suppliers note that they are seeing fewer rescue missions to fix past failures.

In 2009, ISP launched a drug solubility initiative around capabilities in ingredients and processing technologies developed over several years. Bee says the response has been good, driven in part by large companies outsourcing more to third parties, especially to those with specific technical expertise. Smaller drug companies see an opportunity as well, he adds, “and we are seeing interest emerge among generics companies struggling to develop formulations.”

At the same time, competition is on the rise as more custom manufacturers add equipment and capabilities. Beyond the ingredients and technology for making solid dispersions, Bee points out, ISP can handle stability studies, quality analysis, and manufacturing of final dosage forms for clinical development and commercialization. And whereas a big pharma company might deal with 15–20 intractable compounds over any five-year period, in that same time, “we would have worked on more than 100 different poorly soluble compounds, and so we have a huge knowledge base of how to handle different situations,” he says.

Under its initiative, ISP has opened a solubility center at its Hyderabad, India, facility (C&EN, Nov. 30, 2009, page 18). The firm has joined with German equipment maker Coperion to advance hot-melt extrusion in the pharmaceutical market. Their focus will be on developing ingredient and processing combinations for robust and scalable production.

As a complement to melt extrusion, ISP also offers spray drying for creating solid dispersions. In 2004, ISP acquired a cGMP spray-drying facility in Columbia, Md., from the Danish equipment firm GEA Niro. Similarly, although Evonik is investing a lot in melt extrusion, it also operates spray dryers in Japan.

The choice between extrusion and spray drying is generally determined by what works best for a given API in terms of processing parameters, cost, and final dosage requirements. Like extrusion, spray drying employs polymer and drug combinations, and it can work with heat-sensitive APIs that can’t undergo hot-melt extrusion. Yet suppliers of extrusion technology point out that they’ve developed polymers that can be processed at lower temperature.

Spray drying is a fast way to produce powders that allows precise control over particle size and shape. Solid dispersions are made in a spray dryer by coprecipitating a polymer and the drug. After finding a workable mix of drug, polymer, solvent, and the right processing conditions, the solution is atomized into droplets and heated in a drying gas. In fractions of a second, the liquid evaporates, and the particle—formed before the drug is able to crystallize—falls out of the drying chamber and is collected.

In 2004, GEA Niro opened its Pharma Test Station, in Copenhagen, after seeing that drug and API manufacturers were becoming more interested in trying spray drying. More recently, the company began offering contract spray-drying services from its cGMP facility. Under a partnership, GEA Niro allows BASF to use the facility for its customers’ projects.

The station includes a lab-size unit for initial tests and preparation of small quantities, and a larger one suited for making many kilograms of material, explains Michael Wahlberg, test and development head at GEA Niro. At the station, analyses of the kinetics of drying can help model the process on a droplet of material and determine what the product will look like when it is made in a large spray dryer.

As an equipment supplier, GEA Niro has the goal to sell spray dryers, Wahlberg readily admits. He hopes the availability of the test station will lower what he calls the “entry fee” for companies moving into spray drying. “In order for spray drying to be more widely used in the industry, there must be an opportunity for companies to test ideas and have clinical material produced before they invest a lot of money in their own facilities,” he says.

Bend Research knows about large facilities. The Bend, Ore.-based firm developed the spray-dried solid dispersion process for Pfizer’s torcetrapib, which was to be the blockbuster successor to Lipitor until it was halted in Phase III development. Pfizer invested $90 million to build a dedicated commercial-scale spray dryer in Loughbeg, Ireland. In 2009, Portugal’s Hovione bought the facility for its contract manufacturing business (C&EN, Dec. 15, 2008, page 16).

“Torcetrapib was a classic example of a drug that wasn’t really ‘druggable’ without a solubilization technology,” Bend CEO Rod J. Ray says. Not only is it on the extreme edge of BCS Class II, with little measurable solubility in water, but Pfizer also wanted to combine it with Lipitor, which made spray drying one of the few available options.

For a decade, Bend worked exclusively with Pfizer but was released from that relationship in 2008. Although Pfizer remains a major partner, it turned over to Bend much of the intellectual property developed during their work together, which includes other drug delivery technologies and methods to deal with highly lipophilic or crystalline materials. Armed with the technology and free to work with others, Bend has built a client base of about 50 pharma and biotech firms over 18 months.

All told, Bend collaborated with Pfizer for 23 years and has been in operation since 1975. “We have actually seen more than 500 compounds,” and more than 28 of them that have benefited from spray-dried-dispersion technology have been in the clinic, says James A. S. Nightingale, Bend’s vice president for applied technology. This number includes about 10 that are or have been in Phase III trials.

Having miniaturized the spray-dried-dispersion process as part of its technology development, Bend can operate at the discovery end of drug development and test spray drying on a few milligrams of material. “We have a package of technologies that we can provide to clients that lets them pick compounds without solubility as a constraint,” Ray says. In addition, Bend claims that its modeling work, which has been validated by experiments, ensures that what is seen at the small scale will translate to larger scales.

Easy scale-up and reproducibility are recognized features of spray drying. “In our own cGMP facility, we made all the Phase III supply for torcetrapib, which was on the order of 10 metric tons,” Ray says. Bend transferred the technology to the plant in Loughbeg and started it up. “Now, when we are applying this technology to other companies’ drugs, we can convince people very easily that this is commercializable technology,” Ray adds.

As a straightforward drying method, spray drying has been around for decades. It appeared on the scene about the same time as lyophilization, or freeze drying, which formulators once preferred because it yields crystalline forms, explains Douglas B. Hecker, particle-design business development director at Hovione. “They thought spray drying wasn’t a gentle process and produced only amorphous material,” he says.

With amorphous materials now looking promising and an understanding that spray drying isn’t so harsh, attitudes have changed. “In addition to solving solubility issues, formulators are looking for ways to create line extensions of products going off patent or to revive products that had failed due to solubility or bioavailability issues,” Hecker says.

According to Filipe Gaspar, Hovione’s director of particle-design R&D, spray drying is less expensive and more reliable than freeze drying. Spray drying requires fewer processing steps than conventional drying methods and offers remarkable flexibility in engineering particle size and morphology.

“You have a fairly wide range of solvents and stabilizers to produce amorphous materials, and you can manipulate the particle size in an extreme way,” Gaspar says. Anything from very fine powders for inhalation to materials for tablets and delicate biologic materials, such as proteins and vaccines, can be processed.

Hovione has spray-drying capabilities in the U.S., Portugal, and Ireland that range from the gram scale to 400-metric-ton-per-year commercial quantities. The company tries to bridge the gap between API production chemistry and formulation by thinking not just about synthesizing the molecule or the final product, but also about the physical attributes of the API itself. This approach fulfills a development niche and has practical implications as well.

“We can integrate the process chemistry and particle engineering so that the solvent at the last step of the chemistry is a suitable solvent for the spray-drying step,” Gaspar explains. “So we very often don’t isolate the crystalline material and then dissolve it in a different solvent to do the particle-engineering step.” The solvent used in the spray-drying process can also be recovered.

Spray drying is a good example of a technology that can solve problems, points out Guy Villax, Hovione’s CEO. “The pharma industry has so many challenges and increasingly needs specialized techniques to solve them,” he says. “It’s interesting that people are trying to develop new molecules and that the molecules themselves are just not ‘good enough’ to be drugs.”

It’s no longer possible for large companies to have all the technologies and expertise they might need in-house, Villax says, which is why he believes outsourcing works. “It is much easier for a contract manufacturer to invest in an emerging technology,” he says, “because there is much less risk when you can serve all the market and have more compounds to address.”

Ann M. Thayer