On Time Delivery: Challenges of Controlled-Release Formulations

Controlling the rate and/or site at which an API is released provides drug developers with new ways to create medicines that are kinder to patients, yet just as effective. Controlling the release of the API eliminates fluctuations in drug plasma levels, which typically leads to reduced side effects, and also allows for reduction of the number of doses required per day, according to Jessica Mueller-Albers, strategic marketing director for oral drug-delivery solutions at Evonik Health Care.

Ideal controlled-release products enable administration once-per-day for oral therapies and no less than once-per-week up to every six weeks for parenteral treatments, adds Sudhakar Garad, global head of pharmaceutical profiling at the Novartis Institutes for BioMedical Research. Controlled-release doses are also easy to swallow or administer, cost-effective, stable at room temperature for at least two years, and easy to pack and ship.

Other important properties, observes Mueller-Albers, include an excellent retardation effect at low polymer doses, very good tableting behavior, no ethanolic effect on the swelling properties of APIs to avoid dose dumping if a patient consumes alcohol, and thin polymer layers to ensure short processing and coating times.

Achieving these goals can be challenging given the evolving properties of APIs and the increasing desire to develop more targeted medicines. Fortunately, there is a wide range of controlled-release mechanisms available today.

Consistency is key

Successful controlled-release formulations provide for drug release over a defined period of time at a specific rate and at targeted locations, such as the gastrointestinal (GI) tract, skin, muscle, etc., according to Simon Chen, vice president of Bora Pharmaceuticals.

The most important property when designing a controlled-release formulation, asserts Brad Beissner, development scientist II with Metrics Contract Services, is to ensure its robustness of API release, particularly for APIs with a narrow therapeutic range.

“A well-formulated controlled-release formulation is designed to release the drug in a reliable and consistent manner at a predefined release rate and at the optimum site of absorption for its activity,” says Anil Kane, global head of technical scientific affairs, Pharma Services, at Thermo Fisher Scientific. It is critical that the formulation is consistent in performance in global patient populations, age groups, and disease states.

Robustness with respect to consistency of manufacturing is also critically important for controlled-release formulations, according to Ron Vladyka, director of scientific services, oral and specialty delivery at Catalent. “The defining factor that progresses the dosage unit from a prototype to a commercially viable product is its ability to be repeatedly manufactured in a commercial setting,” he says.

Drug release must also be consistent, predictable, and reproducible across population profiles, according to Firouz Asgarzadeh, vice president of pharmaceutics at BioDuro. Predictable release profiles, he notes, make it easier to determine the number of doses required to maintain therapeutic levels of an API in the plasma of a patient and stay below toxic levels. Robust reproducibility across a large spectrum of patients regardless of intra-patient variability is necessary to avoid the need to personalize each drug for every patient, Asgarzadeh adds.

The release rate of the API in the appropriate location along the digestive tract must also be controlled in a precise and reproducible way to achieve optimal bioavailability of the drug after oral administration and ensure a reproducible clinical response, according to Torkel Gren, senior director, technology officer, and strategic investments leader with Recipharm. “To do so usually means that process parameters and excipient qualities must be very carefully and stringently controlled in terms of loading to ensure the desired release rate consistently across the batch and avoid variation during trials and beyond,” he observes.

In general, summarizes Tejas Gunjikar, application development and innovation leader for IFF’s Pharma Solutions business in South Asia, controlled-release formulations should provide the desired and consistent controlled drug release; should be scalable, stable, easy to administer; and should help reduce dosing frequency and side effects, factors that lead to improved therapeutic outcomes for patients. “Such formulations are generally most acceptable and achieve commercial success,” he asserts.

Robustness from preferred excipients

A controlled-release formulation and process, if not carefully designed, could likely result in inconsistent drug release, resulting in variability in therapeutic response, dose dumping, and/or quality rejects. Dose dumping can occur if the controlled-release mechanism does not work, potentially resulting in side effects or toxicity in cases where the drug has a small safety window, according to Kane. In addition, if the drug-product manufacturing process is not robust, quality rejects can result, including deviations, out-of-specifications, and batch rejects, all of which can lead to manufacturing and/or financial losses, he adds.

Building robustness into the drug product begins early in formulation development with the selection of robust excipients, according to Vladyka. “In general, the selection of excipients for controlled-release dosage forms is performed in conjunction with the quality target product profile and physical and chemical properties for the drug substance, but is governed by the technology being employed to manufacture the controlled-release units,” he says.

Additional refinement or selection of critical excipient properties may be needed to modulate the controlled or localized drug-substance release, such as further sizing of core beads for a layering process or the selection of specific lots of polymer based on functional group substitution values. In some cases, a combination of different polymers with different molecular-weight distributions, degrees of substitution, and other characteristics—all of which must be carefully controlled—are necessary to achieve the desired API release rate, notes Philippe Gorria, senior director of formulation development for Recipharm.

“Regardless, the impact of the excipients sets a firm foundation for the optimization and development of the drug product’s formulation and process, enabling the development of a robust product that can be reliably manufactured in a commercial environment,” Vladyka states.

Designing the controlled-release dosage form using the most appropriate mechanism or principle of drug release is key along with the choice, quality, and quantity of the critical functional excipients, Kane remarks.

The most preferred excipients for a successful controlled-release formulation deliver a high degree of reproducible performance and are safe for use for oral controlled release, states True Rogers, senior scientist in IFF’s Pharma Solutions business. Examples of such materials are cellulose derivatives including hydroxypropyl methylcellulose (HPMC), ethyl cellulose, cellulose acetate phthalate, etc., and synthetic excipients such as polyethylene oxides and polymethacrylates. Certain naturally derived excipients based on seaweeds and natural gums are also used, but to a lesser extent, according to Rogers.

Because 100% synthetic excipients demonstrate less batch-to-batch variation with greater degree of modulation and control, they are used more often to achieve robust controlled-release formulations, Asgarzadeh notes.

“Ultimately,” asserts Gorria, “controlled-release excipients must be suitable for the manufacturing process, suitable for controlling drug release, and available in a defined, reproducible quality.”

Controlling release with excipients

Although excipients are traditionally thought of as inactive ingredients, they do play functional roles in controlled-release formulations. It is therefore critical, stresses Asgarzadeh, to have an excellent understanding of the material science and structural properties of selected excipients to overcome the various challenges faced by formulators. “Wisely and judiciously selected excipients will facilitate achieving the desired release profile of a controlled-release drug product, which ultimately affects the targeted therapeutic effects of the drug to a patient,” he says.

Kane also stresses that while the selection of the excipients with the proper functionality and their corresponding levels in the drug-product formulation are critical to the controlled-release drug-product performance, a deeper understanding of how variability in the excipients can affect drug-product performance and the proposed control strategy is an important consideration as well.

Functional excipients that have a direct impact on the performance of the dosage unit and its robustness include polymers, pH-modifying agents, and surfactants, which are used to control and mitigate negative factors when combining multiple enabling and controlled-release technologies, according to Vladyka. He adds that suitable binary or ternary polymer mixtures can inhibit or delay recrystallization of an amorphous drug substance. In addition, the availability of various excipient types and grades enables optimization of the performance of the API in the controlled-release formulation and delivery system being developed.

Furthermore, according to Chen, different excipients can be used not only to help modify the release rates of APIs using the same release mechanism, but to modify the release rates of APIs produced using different manufacturing processes, such as coating, mixing, hot-melt extrusion (HME), spray drying, and more.

“An advantage of using versatile excipients or polymers from an experienced provider is that these can be applied to a broad range of drugs and used for different formulation approaches such as diffusion-based or matrix systems, as well as in different process technologies like granulation, coating, tableting, and HME,” Mueller-Albers agrees. She also notes that excipients with long track records that have been investigated in numerous in-vivo trials and used in marketed products provide a strong basis for successful in vitro-in vivo correlation (IVIVC).

For high-dose controlled release formulations, Garad notes that there are a few special excipients that play an important role in enabling higher API loadings.

It is important, though, that excipient suppliers thoroughly understand their manufacturing processes and provide quality-by-design (QbD) samples that represent the ranges observed for critical material attributes, such as polymer molecular weight, relative substitution levels, particle size, etc., Beissner asserts.

Formulators can be proactive, as well, Beissner says. For instance, for hydrophilic matrix tablets, having at least 25% by weight of the formulation, the rate-controlling polymer helps limit the effects of any naturally occurring raw material variations and ensures tablet-to-tablet release uniformity in the batch. Designing sustained-release coatings to a specific mg/cm2 coating thickness based on surface area of the substrate, meanwhile, makes scaling up the film-coating process easier and provides greater assurance of repeatable results.

Release technology drives excipient selection

Excipients used on controlled-release formulations are constituted of two main classes: matrix and reservoir systems. The mechanism that controls the release differs for both systems and by matrix solubility (hydrophilic or hydrophobic), explains Joao Marcos Cabral de Assis, global technical marketing manager for pharma solutions within BASF’s orals platform.

Excipients that can form thin films and tablet matrices are particularly applicable, according to Gorria, because they can control drug release by limiting drug dissolution and/or drug diffusion, or even through osmotic pumping effects. Sensitivity to pH will also impact excipient selection for drug formulations intended to target a specific location within the intestinal tract. Controlled-release formulations are typically achieved by utilizing high-molecular-weight, water-soluble polymers to form hydrophilic matrix tablets or by film coating using predominately water-insoluble polymers, according to Beissner.

The majority of controlled-release drugs are formulated in hydrophilic matrices that release APIs by drug diffusion and matrix erosion. Cellulosic polymers such as HPMC, hydroxypropyl cellulose, hydroxyethyl cellulose, and methylcellulose are the most common polymers used in extended-release formulations. Alginates, carbopol, and gelatin are less common examples of these materials.

Hydrophobic matrices release APIs through drug diffusion because the matrix is water-insoluble and does not erode. API solubility is consequently a critical factor for the success of these formulations, according to Assis. He points to carnauba wax, cetyl alcohol, hydrogenated castor oil, microcrystalline waxes, ethyl cellulose (EC), stearic acid, and polyvinyl acetate (PVAc) as examples of lipophilic matrices.

The selection of a hydrophilic or hydrophobic matrix such as pH-dependent or pH-independent polymethacrylate is mainly determined by the solubility of the drug because a potential self-retardation effect of the drug at higher pH will have an influence on the release kinetics, according to Mueller-Albers. The same is true for highly soluble drugs that may require strong retardation during stomach passage.

Soluble components are often added to lipophilic matrices and insoluble film coatings to act as pore formers to better adjust drug release. Typical pore formers are povidones (polyvinyl pyrrolidones [PVPs]), polyethylene glycol-polyvinyl acetate (PEG-PVAc) grafted copolymers, sugars, and PEGs.

Reservoir systems consist of a nucleus containing the drug, which can be multi-particulates or a single tablet coated with an insoluble film. Drug release in these systems, says Assis, is carried out exclusively by diffusion and is modulated through film layer thickness, permeability modifiers, and added core components that alter the water-attractiveness. The application is mainly served by insoluble film-forming excipients such as methacrylates, EC, and PVAc.

To choose the right excipient, Mueller-Albers recommends that formulators consider the nature of the API, such as its solubility, charge, etc.; the type and design of the dosage; the strength and duration of the retardation effect; the preferred manufacturing process (i.e., direct compression, granulation, coating, HME, spray drying, etc.); and whether there is a need for easy swallowability, such as for pediatric and geriatric patients.

A thorough understanding of the functionality and material properties of polymers is key to the successful design of controlled delivery, specifically for matrix and osmotic zero-order drug release, adds Kane. For instance, Chen comments that for delayed-release formulations, pH-dependent excipients such as methacrylate polymers will provide gastro-resistant functionality; EC would be the choice for pH-independent controlled release such as with multi-particulate drug-delivery systems (e.g., pellets within a capsule); HPMC would be the main choice for monolithic controlled-release delivery systems; and poly(DL-co-glycolide) (PLGA)-based polymers would be preferred for microspheric depot injection formulations.

As with most formulations, Beissner adds that drug solubility plays a major factor in excipient choice. “Lower-molecular-weight polymers are generally used to generate a more erosion-based drug-release profile for low-solubility drugs, while higher-molecular-weight polymers that swell more and afford a diffusion-based drug-release profile are paired with high-solubility drugs,” he explains. The rate of API release from a sustained-release coating is, meanwhile, modified by changing the ratio of the water-insoluble and water-soluble polymers in the formulation and the film coating thickness.

In addition, Gorria adds that for a hydrophilic matrix tablet, powder flow and compatibility will be important while for a product comprising coated pellets, the polymer must be sprayable and generate a strong thin film on each pellet. It also depends on whether API release will be restricted by slow dissolution, by forming a semipermeable membrane, or through a gel.

Other guiding factors can include anticipating the patient characteristics of the target population, such as in the case of pediatric formulations for which excipient options can be limited somewhat because of safety concerns and the availability of process equipment, according to Vladyka. “Available process equipment can dictate the type of excipients that will be used in the manufacturing process,” he explains.

For instance, Assis notes that for poorly compressible APIs, PVAc can provide the plastic deformation needed to increase the compressibility and allow for simple direct compression, saving process time and costs.

Similarly, EC coatings require large amounts of plasticizer to achieve the necessary film elasticity, which leads to formulation and process complexities, according to Assis. In addition, while some aqueous EC dispersions are available, they have long curing times and require high temperatures, thus most EC coating solutions require the use of organic solvents. PVAc-based coatings, he observes, as aqueous dispersion films, are attractive alternatives with high flexibility, pH-independent drug release, lower curing temperatures, and lower dose-dumping risk.

Finding the right starting formulation

The formulation scientist faces several challenges when formulating a controlled-release drug product. These challenges, according to Gunjikar, are due to the properties of the drug, such as its solubility, dose, handling, processability, interactions with other components of the formulation, and the need for delivery to a site/region in the body at a predetermined rate; incomplete API release; and most importantly the ability to provide reproducible performance for consistently attaining the desired therapeutic outcome.

Mueller-Albers agrees that the main challenge to formulating controlled-release small-molecule drug products is that the properties of the API influence the release kinetics, and therefore, it is not so easy to find the right starting formulation.

In the formulation design of a controlled-release drug product, Kane adds that it is essential to evaluate the excipient variability on drug-product performance, and so it is critical to identify the most impactful material properties of the functional excipient such as a polymer (chain length, viscosity, swelling behaviour, etc). “This excipient variability understanding can then be combined with the knowledge of each of the API properties and the process parameters used to manufacture the drug product and to develop an appropriate control strategy that ensures consistent supply of safe and efficacious drug product,” he asserts.

“Formulator experience is crucial to address the challenges in controlled-release small-molecule drug products. For formulators who have limited experience with controlled-release dosage forms, partnering with a supplier that can provide the right excipient, technology, and process on a short timeline is essential. When formulators work under extreme time pressure, it is also important to have a platform solution that can be applied to several candidates,” Mueller-Albers says.

Close collaboration between formulators and ingredient providers during product development and scale-up could identify ingredients and properties that are critical not only to quality, but also to performance, agrees Gunjikar. “Defining both quality and performance design spaces leads to a more robust medicinal product,” he says. Industry-leading excipient vendors are an underutilized resource during the development of dosage forms, and their knowledge and experience with the application of excipients can be used to solve issues as they arise, Ron Vladyka, director of scientific services, oral and specialty delivery at Catalent, adds.

Most important is starting the initial formulation development of controlled-release dosage forms with knowledgeable partners, such as excipient suppliers, Mueller-Albers says. “Establishing such partnerships very early on can accelerate development because the right formulation and process parameters can be found more quickly. We have found that early exchange between an excipient manufacturer and formulator helps overcome challenges such as curing of aqueous controlled-release coatings by in-process curing solutions and avoiding alcohol dose-dumping by modulating formulations,” she explains.

Achieving IVIVC, zero-order release, and robustness

One of the biggest challenges for controlled-release formulations is to achieve IVIVC. “The relationship between an in-vitro property of a dosage form and its in-vivo response is especially important for controlled release oral formulations,” asserts Mueller-Albers. Through the successful development and application of an IVIVC, in-vivo drug performance can be predicted from its in-vitro behavior. “The establishment of a meaningful IVIVC can provide a surrogate for bioequivalence studies, improve product quality, and reduce regulatory burden,” she adds.

Establishing this correlation can be difficult, however, due to absorption variations in the fed and fasted states for each patient and differences in intestinal tract transit, gut metabolism, etc., patient-to-patient, adds Assis.

Obtaining a zero-order release can also be considered a challenge for formulators. “Push-pull systems are an alternative for achieving this type of release, but the technologies required for their manufacture are so complex that most companies steer away from these systems,” notes Assis. Recently, though, he remarks that the use of a combination of functional hydrophobic matrix polymers (e.g., PVAc) blended in the appropriate proportion with a gastro-resistant polymer such as methacrylic acid and ethyl acrylate copolymer that acts as a pH-dependent pore former makes it possible to ensure linear release.

One challenge that continues to create issues for formulators is the difficulty in achieving targeted release of API in the lower intestine, according to Gorria.

Stability in various forms can also pose difficulties. For instance, changes in dissolution characteristics are often observed when the drug product is stored, notes Thorsten Cech, pharmaceutical technology application expert and manager of BASF’s European Pharma Application Lab. While curing can minimize these risks, this property remains a potential critical material attribute that requires thorough investigation during product development.

Ensuring the robustness of API release can be challenging as well due to the inherent variability of the polymers used in controlled-release applications, according to Beissner. “It is important that controlled-release formulations can withstand this lot-to-lot raw-material variability,” he says.

To ensure robust and reproducible release with minimal inter- and intra-patient variability over the intended extended period for controlled release, Asgarzadeh observes that the polymer excipients used in these formulations need to remain intact throughout the GI tract, efficiently facilitate API diffusion from the core of the drug product through the excipient membrane over time, release the drug predictably independent of patient diet, and provide release of the therapeutic level of the API without undergoing any physical transformation.

Formulating high-dose controlled-release drugs

Dose is the biggest challenge from Garad’s perspective. “In controlled-release formulations, the dose should be lower than that for conventional drug products so that it is possible to generate a formulation of a palatable size whether given orally or administered parenterally,” he observes. The final dosage form—a tablet or capsule, for instance—may be very large once you have combined several doses and added release controlling excipients, explains Gorria. Large tablets and capsules can be difficult to swallow for children and elderly patients with dysphagia, leading to reduced patient compliance and thus the effectiveness of the treatment.

For this reason, Garad notes that molecules with a narrow therapeutic window are typically not ideal candidates for controlled release. Very low-clearance molecules are not generally good candidates either, as they keep accumulating, which can lead to side effects.

Overcoming solubility challenges

APIs with very high or very low solubility create additional challenges because it is difficult to control their release profiles with excipients, according to Chen. For APIs with poor solubility, Vladyka remarks that there is a need to conjoin enabling technologies to increase the apparent solubility of the drug substance within a controlled release form. “In some cases,” he says, “these two technologies may not have compatible manufacturing processes and their selection could limit the preparation of controlled-release dosage forms.”

Specifically, Vladyka points to higher-energy-state techniques for improving drug substance solubility, which he notes may not be suitable for aqueous or organic solvent-controlled release processing because their use may cause re-crystallization of the drug substance and a decrease in solubility. Use of higher-energy-state APIs in drug reservoirs for diffusion-based drug release can potentially result in recrystallization of the API, which would change the release profile.

Despite these concerns, Cech points to the formation of amorphous solid dispersions (ASDs), particularly via hot-melt extrusion (HME), as an attractive solution for poorly soluble APIs. “HME has been shown to improve solubility and bioavailability and modulate release through the simultaneous introduction of controlled-release functionalities,” he explains. The controlled-release behavior can be achieved not only through careful selection of the polymer used to form the ASD, but also through optimization of porosity of the tablets produced from the compacted extrudates.

Systematic approach benefits

While it is possible to design a molecule to fit a controlled-release formulation, that is not usually feasible. The current practice, according to Garad, is to take an existing molecule and fit it into a controlled-release dosage form platform technology. “The key is to combine the right physicochemical properties with the right pharmacokinetic properties of the molecule and the right controlled-release technology and the ideal polymer,” he states.

Proactive identification of critical material attributes and their impact on drug release is essential, Cech adds. The interplay between these attributes and process variables (temperature, compression pressure, etc.) and material incompatibilities also needs to be studied.

“Depending on the API’s solubility and other physiochemical properties of the drug, different approaches can be used by formulators to ensure the likelihood of success and to achieve the expected drug-substance release. Considerations such as hydrophilic or hydrophobic matrices, film- and pore-formers, feasibility of the manufacturing process, and product stability can be part of QbD programs for systematic drug product development,” Cech observes.

Vladyka also highlights the importance of using knowledge and understanding about the drug product under development to guide the choice of approach and at what stage in the process to begin. A successful strategy takes a combination of deep formulation knowledge and empirical testing, adds Asgarzadeh.

Cech notes that using alternative methods to investigate processing such as determining the porosity flowability, compactability, and tabletability and subjecting non-optimized formulations to stability testing early on to select the most robust ones might be a good tactic to assure the quality and safety of final controlled-release drug products.

Information can be collected using pharmacokinetic modeling and solubility studies in various media including in simulated gastric fluids (to determine logP, dose, and solution stability). Formulation and process development can range from a broad multi-dosage form approach to a single technology, highly focused development plan.

Gren is in favor of investigating several formulation principles and excipient combinations to identify the most appropriate approach for the needs of a given project, and also says it is essential to determine the compatibility between all components of the future formulation to avoid degradation phenomena (polymer/polymer and/or polymer/drug substance).

Equally important, says Vladyka, is using high-quality excipients from industry-leading suppliers that have well-characterized quality attributes throughout the development lifecycle. Because excipients play a direct role in the controlled-release profile itself, Asgarzadeh adds that they should be selected based on prior experience and demonstrated properties that satisfy the needs of the API itself. “The ability to test excipients in efficient animal models increases the probability of identifying formulations that will succeed in the clinic by helping to determine which excipients work best both in vitro and in vivo, providing relative prediction for human release profiles,” he says.

“As all drug substances are different, there is no one-size-fits-all solution,” Gren concludes. “Once a suitable prototype is identified, therefore, a design-of-experiment approach is useful in establishing a formulation and process parameter space that gives robust drug-release characteristics. Formulators can then be confident that they understand how the formulation will perform in a variety of real-world situations (several physiologic media), which allows them to refine the finished product to ensure consistent performance, regardless of real-world conditions,” he says.

About the author

Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology.

Article Details

Pharmaceutical Technology
Vol. 45, No. 9
September 2021
Pages: 16–22

Citation

When referring to this article, please cite it as C. Challener, “On Time Delivery: Challenges of Controlled-Release Formulations,” Pharmaceutical Technology, 45 (9) 2021.