studies will find the perfect partner for your API
ISTOCKPHOTO.COMIn early drug development, excipient compatibility studies are the first formulation development step, providing a rational basis for identification of low-risk excipients with physical and chemical compatibility to the drug substance. A well-constructed drug excipient compatibility study takes preformulation data, dosage strength, final dosage form, method of manufacturing, and animal study data into account, assigning a relative risk level to each excipient within a functional class.
Assessment of excipient risk level is influenced by guidance from the Food and Drug Administration’s Center for Drug Evaluation and Research regarding approved excipient level, as well as formulator familiarity. Drug excipient compatibility studies are critical for well-formulated final dosage forms where the drug may be in contact with one or more excipients during process scale-up from clinical trials through commercial to consumer. Performing these studies at the early development stage has the potential to both accelerate drug development and minimize the risk of drug product stability failure or regulatory delay.
The ability to understand and overcome challenging physicochemical and physical properties of a drug may prevent costly development delays that might be caused by dissolution, bioavailability, scale-up, or stability issues. Another advantage of excipient compatibility studies is the flexibility to change from dilution blend to wet granulation techniques, or vice versa, if required.
The strategy for excipient selection described in this article—for drugs in capsule or binary blend tablets—can help streamline your path to commercialization.
Why Perform Studies?
Understanding the physicochemical and physical properties of a drug is critical to successful early phase development efforts. The physicochemical properties of a drug—chemical structure, physical form, particle size, method of manufacturing, temperature or humidity level, light, and oxygen—are known to affect stability and fuel chemical reactions, such as Maillard, hydrogen bonding, ring opening, salt formation, and complexation. From a wet granulation process point of view, the physical changes in a drug, particularly polymorphic transition or formation of amorphous material due to the addition of water, are critical to choosing a manufacturing process.
Fueled by positive preclinical animal study data, product development teams at both emerging and large pharmaceutical companies often find themselves under pressure to reach Phase 1 studies within an accelerated timeline. Accordingly, formulators select from several options to accelerate drug development, including drug into capsule, drug in bottle, liquid in capsule, and binary blends.1 Formulators keep the end goal in mind, applying drug excipient compatibility studies to develop optimal formulation and manufacturing processes suitable for commercial use.2 Because selected excipients become part of the drug product, formulators conduct drug excipient compatibility studies to optimize conditions for physical and chemical compatibility and to minimize any negative impact of excipient selection on drug product stability.
When evaluating excipients for inclusion in a final dosage form, formulators have a number of options available. Excipient selection studies during the design of Phase 1 clinical formulation are critical for both accelerated drug development and optimal dosage form stability. Well-executed drug excipient compatibility studies can reduce the risk of a stability problem that might cause process dissolution changes, the need for repeat bioavailability studies, method re-qualification or validation, regulatory addenda, and delayed market approval. This article provides a strategy for excipient selection based on understanding the challenges of active pharmaceutical ingredient (API)-excipient interaction in early drug development, with an eye towards streamlining the path to commercialization.
Excipient selection should be driven by the physicochemical properties of the drug, method of manufacturing, and pharmaceutical dosage type. The dosage form will dictate the choice of fillers, release modifiers, binders, disintegrants, lubricants, glidants, surfactants, coloring agents, coating agents, and acidifiers. A typical study includes at least two or three excipients per type so that any unforeseen compatibility issue can be overcome by switching to an alternative excipient. Because all the excipients are projected to be part of the final dosage form, the study may be started in one phase. Doing so is both time and cost effective because analytical testing is performed at one time for all the samples.
Well-executed drug excipient compatibility studies can reduce the risk of a stability problem that might cause process dissolution changes, the need for repeat bioavailability studies, method re-qualification or validation, regulatory addenda, and delayed market approval.A typical study will contain approximately 20 excipients but may be reduced for capsules, in which case selection of coloring and coating agents may be prolonged. Researchers must take into account the pH-solubility profile and preclinical animal study data because an enteric coating or a targeted coating agent is dosage form-dependent. A recent study provides placebo stability data of hydroxypropyl methylcellulose capsule shell versus enteric coating agents such as Aquacoat CPD and Sureteric over a basecoat of Opadry [Colorcon].3
It is optimal to perform the drug excipient study in both dry and wet conditions, regardless of whether there is a pre-defined manufacturing method in place. The wet method involves addition of 20% water to the wet samples. In a typical binary blend study, the API is placed with filler and release modifier at a 1:1 proportion, while the disintegrant, lubricant, glidant, surfactant, coloring agent, coating agent, and acidifiers are placed at a 10:1 proportion. Serajuddin and colleagues evaluated a statistical design method that involved a two-phase study.4 The first phase involved drug with fillers and lubricants. Based on the results, one primary filler and lubricant were chosen to include binders and disintegrants in the second phase study.
Despite the importance of drug excipient compatibility testing, no generally accepted method is available as a predictive tool. Most of the methods reported in the literature are conducted at high temperature and humidity at 40°C/75% relative humidity (RH)—typical International Conference on Harmonisation conditions—and at normal 25°C/60% RH as backup stability conditions, or in an oven at 50°C and 60°C. A temperature of 50°C could be justified, but exposing the blend to 60°C, a temperature to which the blend will never be exposed, is arguable. This is especially true in cases in which the excipients possess low melting point characteristics that eliminate them from inclusion in the drug product. Consideration to open and closed vial conditions is worthwhile as a means to speed this process.
Excipient selection should be driven by the physicochemical properties of the drug, method of manufacturing, and pharmaceutical dosage type. The dosage form will dictate the choice of fillers, release modifiers, binders, disintegrants, lubricants, glidants, surfactants, coloring agents, coating agents, and acidifiers.For the 40°C/75% RH storage condition, the recommended pull points are one, two, four, and eight weeks, whereas for 50°C and 60°C, the stability pull points may be up to two and four weeks, respectively. At each sample pull point, a quick visual observation certainly provides supporting information for laboratory assay and impurities data. Further understanding of the chemical change can be confirmed by tests like differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy, nuclear magnetic resonance, and X-ray powder diffraction (XRPD). It is arguable whether these tests are required at this phase of development or should be considered depending on the method of manufacturing used later in formulation development. A benefit is that the tests may provide additional data to assist in decision making.
An extensive loss of potency, significant growth in impurities, or an unknown chemical degradation may result in regulatory agency questions prior to approval. A change in physical appearance, along with chemical degradation, signals the potential for product failure. High-performance liquid chromatography (HPLC) analysis of chemical drug degradation is generally more favorable; testing at various points in time can reveal the appearance of new peaks or significant peak growth.
Additional methods of analysis include DSC, thermogravimetric analysis (TGA), and XRPD. DSC is used to detect changes in the physical appearance, TGA indicates the amount of water associated, and XRPD can reveal other chemical changes in addition to dehydration. DSC data with changes in melting enthalpy, peak shape, peak area of transition, and additional new peaks will confirm HPLC analysis of chemical drug degradation. n
Kadri is manager of preformulation and formulation development at Xcelience LLC. Reach him at (813) 637-6049 or firstname.lastname@example.org.
1. Kadri BV. Recent options for phase 1 formulation development and clinical trial material
supply. Pharm Technol Outsourcing Resources supplement. Pharmtech.com Web site. August 2, 2008. Available at: http://pharmtech.findpharma.com/pharmtech/Formulation+Article/Recent-Options-for-Phase-1-Formulation-Development/ArticleStandard/Article/detail/541994. Accessed February 24, 2009.
2. Chang D, Chang R. Review of current issues in pharmaceutical excipients. Pharm Technol. Pharmtech.com Web site. May 2, 2007.
Available at: http://pharmtech.findpharma.com/ pharmtech/Excipients/Review-of-Current-Issues-in-Pharmaceutical-Excipie/ArticleStandard/Article/ detail/423551 . Accessed February 24, 2009.
3. Kadri BV, Greene MB. Enteric coating and
stability of aqueous enteric systems on HPMC capsules. Paper presented at: AAPS Annual Meeting; November 16-20, 2008; Atlanta, Ga.
4. Serajuddin AT, Thakur AB, Ghoshal RN, et al. Selection of solid dosage form composition through drug-excipient compatibility testing.