Deanna Mudie, principal scientist at Lonza looks at how to increase the robustness of oral drug products and accelerate their development with biorelevant dissolution media.
Oral delivery is a common route of administration for pharmaceutical drug products. To be effective, oral drug products must dissolve in gastrointestinal (GI) fluids and permeate across the GI membrane. Depending upon the drug and formulation properties and physiology of the target patient population, these processes can determine how quickly the drug appears in the bloodstream 1, 2. For efficient development of robust drug products, developers need rapid, accurate methods to evaluate how the interplay between formulation and GI physiology will affect drug-product performance.
In vitro dissolution testing is the gold standard for assessing oral performance throughout the drug product lifecycle 3. In vitro dissolution testing falls into three categories: (1) quality control (QC); (2) biorelevant; and (3) clinically relevant, with potential overlap between the three 4. Whereas QC testing is used for such purposes as detecting drug-product changes during manufacturing, biorelevant testing is used to guide formulation selection and clinically relevant testing is used to link in vitro and in vivo pharmacokinetic data 4. By using dissolution media to support biorelevant dissolution testing, drug developers may have success facilitating right-first-time pre-clinical and clinical formulations, and ultimately enable low cost and high speed to patients.
Evolution of biorelevant dissolution media
Dissolution testing apparatuses have been used for decades and have improved with our knowledge of GI physiology 5-7. Likewise, the dissolution media used within these apparatuses have evolved, expanding the range of media properties and better simulating compositions of GI fluids. United States Pharmacopeia (USP) buffers, such as 50 mM phosphate have been used widely since their development in the 1950s 5, 8. Rather than mimicking the properties of GI fluids, they serve as simple, practical buffers for QC testing and can adequately assess the dissolution rates of high-solubility Class 1 and 3 drugs in the Biopharmaceutics Classification System (BCS) 1, 9.
Newer dissolution media with increased accuracy and complexity have been developed to more closely mimic GI fluids. These media include versions representative of fasted and fed humans and of preclinical species such as dogs 10-18. Properties of in vivo and simulated GI fluids can have a profound impact on dissolution, particularly for low-solubility BCS Class 2 and 4 drugs 1, 9. Use of these new dissolution media in a biorelevant dissolution apparatus is designed to predict in vivo drug performance, ideally coupled with in silico modelling 19.
Drug formulation-GI fluid property interplay
Important GI fluid properties include pH, buffer capacity, ionic strength, and presence of endogenous bile salts (BS), phospholipids (PL), cholesterol, and dietary fats and carbohydrates. These properties can vary significantly in vivo as a function of species, GI region, prandial state, age, disease state, and natural variation among and within individuals 2, 20. In addition, these properties vary significantly among different in vitro dissolution media available to formulation scientists.
Drug and formulation physicochemical properties impact dissolution, even within the low-solubility BCS Class 2 and 4 drug categories 9. Key drug properties impacting dissolution include acid/base character, pKa, intrinsic solubility, and lipophilicity 9, 20-22. Key formulation properties include the presence of acidic or basic excipients and their pKa values, and the presence of polymers with the tendency to swell 23, 24.
For drugs and excipients, acid/base character and pKa influence the extent of drug ionization and, therefore, solubility across the GI pH range. For example, acidic compounds are more soluble at moderate to high pH, but basic compounds are more soluble at low pH. Acid/base character, pKa, and intrinsic solubility impact the extent of surface-pH alteration by charged drug or excipient species, which can impact drug and excipient solubility at the particle interface. The higher the surface-pH alteration, the slower the dissolution 9.
Drug lipophilicity, together with charge, size, polarity, and flexibility impact the extent of drug solubilization in mixed lipidic aggregates composed of endogenous BS and PL, cholesterol, and dietary fats and carbohydrates. The higher the lipophilicity, the higher the extent of partitioning into mixed lipidic aggregates 20, 22.
This interplay between drug formulation and GI fluid properties is illustrated in Figure 1. As shown, the interplay is focused on solubility of the formulation in GI fluids, in mixed lipidic aggregates, and at the solid particle surface. Understanding this interplay is critical for selecting dissolution media to achieve the intended purpose (e.g., ranking formulations or testing formulation robustness in vivo).
Figure 1. drug formulation and GI fluid properties affecting drug product dissolution
Steps to biorelevant dissolution media test selection
Selecting the optimal dissolution medium can be challenging given the variety of available media and the diversity in drug and formulation properties. A three-step method to select dissolution medium may achieve the desired testing outcomes while reducing time and cost. These steps, described below, are
- Determine the dissolution testing goal.
- Determine the target population(s) of interest.
- Select dissolution media capturing key GI fluid properties affecting dissolution.
1) Determine the dissolution testing goal
The first step in selecting the optimal dissolution medium is determining the dissolution testing goal. A common goal in early development is to rank formulations by predicted in vivo performance so the formulation(s) with the highest likelihood of success can be carried forward into preclinical and/or clinical studies. In this case, the formulator may want to develop a single “discriminating” dissolution test that sets a high bar for achieving a high dissolution rate. For example, a formulator may want to select a dissolution medium pH that is either at the low end (in the case of a weak acid drug) or at the high end (in the case of a weak base drug) of the intestinal pH range, to see how different formulations perform under a condition expected to result in the slowest dissolution rate, to elucidate differences among the formulations 9.
An alternative dissolution testing goal might be to determine the sensitivity of a formulation to various physiological and fluid properties. This approach would allow a formulator to evaluate formulation robustness within the natural GI variation among or within individuals, among different prandial or disease states, or among different populations. A formulator might want to measure dissolution in a range of media with different properties representative of target groups or individuals—for example, a design of experiments probing dissolution rate over the entire range in GI pH, buffer capacity, and type and concentration of mixed lipidic aggregates expected in the target population.
2) Determine the target population(s) of interest
GI fluid properties can vary significantly in vivo as a function of species, prandial state, age, disease state, and natural variation among and within individuals 2, 20. Therefore, the target population for the drug product and for preclinical studies is an important consideration when selecting dissolution media. For example, if a drug product is intended for adult humans, a formulator might select dissolution media representative of adult human salivary, gastric, small intestinal, and/or colonic fluid. If the drug product is intended to be taken with or without food, the formulator might also select fluids relevant to both the fasted and fed states. If a preclinical species, such as rats or dogs, is to be used for assessing early drug-product performance, then dissolution evaluation in fluids relevant to those species should be considered, because variations in fluids among species can result in different dissolution outcomes 25.
3) Select dissolution media capturing key GI fluid properties impacting dissolution
Once the dissolution testing goal and target population(s) have been determined, the formulator can select dissolution media capturing key fluid properties impacting dissolution. The interplay between drug formulation and GI fluid properties can be used as a basis for this selection 9. Although several GI fluid properties impact dissolution, three key properties are (1) pH, (2) buffer capacity, and (3) type and concentration of BS and PL, cholesterol, and dietary fats and carbohydrates. Each of these properties can be tailored to “match” either the range or the average, minimum, or maximum value of the population(s) of interest to achieve the intended dissolution testing goal. Furthermore, when the formulation is not predicted to be sensitive to one or more of these factors, knowledge of the drug formulation—GI fluid property interplay may allow formulators to select a simpler dissolution medium 9.
Case study: Dissolution testing of belinostat amorphous spray-dried dispersion
This case study describes biorelevant in vitro dissolution testing of belinostat amorphous spray-dried dispersions (SDDs). The purpose was to rank formulations for preclinical studies in fasted dogs 24. Belinostat is a BCS Class 2/4 drug with poor aqueous solubility. Its acidic pKa (7.9) renders it virtually non-ionized across the GI pH range and its log P (1.8) contributes to its relatively low extent of partitioning into mixed lipidic aggregates.
Based upon these drug properties, one might expect (1) any single dissolution medium pH to be biopredictive (i.e., pH-independent solubility); (2) any buffer capacity to be adequate (i.e., no change in surface pH due to lack of drug ionization); and (3) inclusion of BS and PL in the medium to result in only a moderate increase in apparent drug solubility.
However, formulation properties must also be considered. In this study, SDDs were prepared with three different polymers: polyvinyl pyrrolidone (PVP K30), polyvinyl pyrrolidone vinyl acetate (PVP VA64), and hydroxypropyl methylcellulose acetate succinate (HPMCAS-M). Although PVP K30 and PVP VA64 are non-ionizable across the GI pH range, HPMCAS-M is an enteric polymer with acidic moieties that result in limited solubility below pH 6, but increasing solubility once ionized above pH 6 26. Therefore, pH and buffer capacity can impact dissolution of the belinostat HPMCAS-M SDD.
An in vitro gastric-to-intestinal transfer dissolution test was performed. SDDs were first exposed to pH 2 medium representative of the low gastric pH range in dogs. After 30 minutes, the formulations were exposed to pH 6.5 (67 mM) phosphate buffer containing BS and PL as the intestinal medium. pH and BS/PL concentration were at average values for fasted dogs. A premade buffer with buffer capacity higher than expected in dogs was used for ranking 25.
SDD performance (based on maximum drug concentration) in the in vitro transfer test is shown in Figure 2a. As shown, the ranking of the SDDs was PVP K30 SDD > HPMCAS-M SDD > PVP VA64 SDD. In contrast, when the SDDs were tested in an in vitro dissolution test using only intestinal medium, the ranking changed. As Figure 2a shows, the HPMCAS-M SDD had the best performance. The reason for the poorer performance of the HPMCAS-M SDD in the transfer test was the poor solubility of HPMCAS-M at pH < 6, which limits release of belinostat at pH 2 and results in particle aggregation before transfer into intestinal medium 24. While slower release of enteric SDDs such as HPMCAS is a common concern, release rates vary with drug loading and drug properties (e.g., acid/base character and pKa).
Figure 2. In vitro dissolution concentration-time profiles of belinostat SDDs from gastric-to-intestinal transfer test (a) and intestinal-only test (b). Dashed lines represent apparent amorphous solubility for each SDD.
As shown in Figure 3, the transfer test correctly predicted SDD performance ranking in dogs, whereas the intestinal medium test did not. Exposure to gastric-medium followed by intestinal-medium pH was critical due to the ionizability of HPMCAS-M. Use of a high (i.e., nonphysiologic) buffer capacity did not alter the ranking of the SDDs, since lower buffer capacity is predicted to reduce the dissolution rate of the enteric polymer, resulting in the same ranking in the transfer test 23.
These results highlight the importance of considering both the drug and excipient properties when selecting dissolution media.
Figure 3. In vivo area-under-curve (AUC) results in dogs versus in vitro AUC from belinostat SDDs in gastric-to-intestinal transfer test (a) and intestinal-only test (b)
Conclusions
In vitro dissolution testing is important for assessing oral drug-product performance. When developing drug-product formulations, selecting dissolution media that can rank or test formulation robustness is paramount. As this article describes, knowledge of key physiological and drug-formulation properties can be combined to select dissolution media predictive of in vivo performance, when used with biopredictive dissolution test apparatuses and, ideally, in silico modelling. This approach can enable right-first-time development, while minimising fluid complexity, which can ultimately reduce cost and increase development speed of medicines. Certain external partners with the right capabilities, including some contract development & manufacturing organisations (CDMOs), may help small and emerging biotech companies approach in vitro dissolution testing to reap maximum benefits when developing innovative drug products.
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