Haste Makes Waste: The Interplay Between Dissolution and Precipitation of Supersaturating Formulations
Contrary to the early philosophy of supersaturating formulation design for oral solid dosage forms, current evidence shows that an exceedingly high rate of supersaturation generation could result in a suboptimal in vitro dissolution profile and subsequently could reduce the in vivo oral bioavailability of amorphous solid dispersions. In this commentary, we outline recent research efforts on the specific effects of the rate and extent of supersaturation generation on the overall kinetic solubility profiles of supersaturating formulations. Additional insights into an appropriate definition of sink versus nonsink dissolution conditions and the solubility advantage of amorphous pharmaceuticals are also highlighted. The interplay between dissolution and precipitation kinetics should be carefully considered in designing a suitable supersaturating formulation to best improve the dissolution behavior and oral bioavailability of poorly water-soluble drugs.
KEY WORDSamorphous formulation kinetic solubility nonsink dissolution testing poorly water-soluble drug supersaturation rate
Therapeutic candidates with poor aqueous solubility pose technical challenges in formulating oral dosage forms during pharmaceutical development. Modern solubilization technologies—with advances in lipid-based, self-microemulsifying, nano-sized, and amorphous formulations, among many others—have equipped formulation scientists with essential tools to develop poorly water-soluble compounds into viable drug products with adequate oral absorption. These enabling formulations can promote oral bioavailability by fundamentally increasing the drug’s equilibrium solubility (e.g., prodrugs), enhancing the apparent solubility by forming drug-carrier complexes (e.g., surfactant micelles), or creating a supersaturated drug solution (e.g., amorphous solid dispersions (ASDs) in water-soluble carriers) during dissolution in the gastrointestinal (GI) microenvironment. In the latter case, precipitation within the intestinal lumen is a thermodynamically favored process owing to the unstable nature of the supersaturated drug solution which provides a driving force for nucleation and crystallization. If extensive supersaturation-induced precipitation occurs in the upper GI tract before the solubilized drug can be sufficiently absorbed, reduced absorption rate and suboptimal systemic exposure could occur. The rate and extent of intestinal precipitation depends on many complex factors that directly affect the duration of drug supersaturation in the GI tract, such as the physicochemical properties of the drug molecules (e.g., pH-dependent solubility, ability to generate supersaturation, crystallization propensity), physiological factors (e.g., permeability across intestinal villi, absorption window, gastric emptying), food effect, excipient effect (e.g., crystallization inhibition), and formulation design (e.g., dissolution rate). During drug development, supersaturating formulations are often subjected to in vitro dissolution testing to gain a better understanding of their supersaturation kinetics and potential in vivo precipitation behavior. In this case, the resulting dissolution profiles under nonsink conditions have typically been characterized qualitatively by an initial rapidly dissolving and supersaturating “spring” with a precipitation retarding “parachute” (1,2). In such a “spring-and-parachute” approach, the design rationales of supersaturating drug delivery systems have primarily been focused on enhancing the dissolution rate, increasing the maximum achievable supersaturation, and prolonging its duration following the dissolution by delaying the recrystallization of supersaturated drug solutions.
In a 2012 commentary, Augustijns and Brewster (12) described a conundrum concerning the “spring-and-parachute” design approach for supersaturating drug delivery systems, in that the higher the desired rate and extent of supersaturation, the more it exacerbates the physical instability of the metastable supersaturated drug solution due to an increased tendency for the solubilized drug to crystallize during dissolution. Specifically, the authors remarked on a general shortfall in correlating the in vitro and in vivo results: Fast dissolution of supersaturating formulations does not always produce better in vivo performance.
Here, we wish to highlight important recent experimental and theoretical evidence to help bridge the gap in our current understanding of the interplay between dissolution and precipitation kinetics of supersaturating drug delivery systems. As stated earlier, the in vivo pharmacokinetic performance of supersaturating formulations is a complex phenomenon which involves many processes that directly affect the duration of drug supersaturation in the GI tract. This commentary aims to address the in vitro in vivo implications of supersaturation generation rate using available literature in vivo data for supersaturating formulations. Through a better understanding of the critical effects of the supersaturation generation rate (i.e., dissolution rate) and the initial degree of supersaturation of amorphous pharmaceuticals on the resulting supersaturation kinetics, it is hoped that improvement of the design of enabling supersaturating formulations for oral drug delivery will emerge.
IN VITRO IN VIVO RELATIONSHIP OF SUPERSATURATION GENERATION RATE
SINK DISSOLUTION CONDITIONS: TO BE, OR NOT TO BE?
The U.S. Food and Drug Administration’s guidance on dissolution testing currently in force for immediate-release oral solid dosage forms dates back to August 1997 (22). In this guideline, the key objectives of dissolution testing include the assessment of lot-to-lot consistency, confirmation of continuous product quality after certain changes (e.g., formulation, manufacturing process), and evaluation of new formulations. While the guideline clearly defines the apparatus, dissolution medium, hydrodynamics of agitation, and other aspects of dissolution methodology, it contains the statement that “sink conditions are desirable but not mandatory” (22), thus allowing flexibility in selecting the dissolution conditions. However, proposing a dissolution method under sink or nonsink conditions at times presents challenges to industry and the regulatory agency, especially for oral drug products containing supersaturating formulations. Current in vitro dissolution testing using compendial methodologies (i.e., United States Pharmacopeia (USP)) is conducted under perfect sink conditions, defined as the volume of dissolution medium at least three times that required in order to form a saturated solution of drug substance (23). It is quite evident that this dissolution method would not be suitable for the direct assessment of enabling supersaturating formulations for the purpose of generating supersaturated drug solutions to improve the oral bioavailability of insoluble drugs. In addition, a physico-relevant dissolution testing involving solid-state analysis is recognized to be particularly important for predicting the in vivo performance (24). Following the advent of real-time and in situ analytical methods for dissolution testing (e.g., derivative UV spectroscopy), it is now possible to quantify drug concentrations in a supersaturated state without the interference of undissolved or newly formed submicron particles, thus allowing the generation of validated dissolution methods under nonsink conditions (25). Dissolution under nonsink conditions can build up drug supersaturation during the dissolution of supersaturating systems as commonly occurred under finite-volume conditions in the GI tract which can trigger the associated nucleation and crystallization events. As such, the application of nonsink conditions in supersaturation dissolution testing is generally recommended in order to evaluate the true performance of supersaturating formulations and to address the tendency for drug precipitation (19,26).
The use of complex solid-state formulations to improve oral bioavailability of poorly water-soluble drugs will inevitably lead to a multitude of dissolution behaviors, which in turn would require a well-defined dissolution methodology to best serve its purpose. To address the key question of how does one compare two nonsink dissolution conditions, the SI value discussed above can be conveniently used to differentiate dissolution methods for supersaturating formulations as it only requires knowledge on the equilibrium solubility (Cs) of the drug in physiologically relevant media (e.g., SGF, FaSSIF, FeSSIF), designated dose amount, and volume of the dissolution medium. Depending on the selected range of SI values (e.g., large, intermediate, or small) for the proposed dissolution method, pertinent information relating to the quality and performance of the test supersaturating drug products could be obtained by analyzing the characteristic trend of the resulting dissolution profiles as described above. Consequently, the dissolution specifications should be adjusted in accordance with the anticipated dissolution behaviors. For instance, single-point specifications may be appropriate to confirm the total drug content and dissolution rate for dissolution methods with high (e.g., Fig. 2a) and intermediate (e.g., Fig. 2b) SI values, respectively. However, for dissolution methods with small SI values which tend to magnify the supersaturation behavior (e.g., Fig. 2c), dissolution specifications would require a full kinetic solubility profile (i.e., multiple points) in order to reveal the underlying dynamics of drug dissolution and precipitation. Using the amorphous fenofibrate-mesoporous silica system with a pore size of 7.3 nm as an example, the dissolution specifications may be set as NLT (not less than) 95% (Q) in 10 min for a SI of 3.56 (Fig. 2a) and NLT 60% (Q) in 30 min for a SI of 0.538 (Fig. 2b) whereas multiple-point specifications including 40–60% in 10 min, 30–50% in 30 min, and 20–40% in 60 min may be needed for a SI of 0.136 (Fig. 2c). In addition, it is noteworthy that the extent of supersaturation generation and the crystallization propensity are all drug-dependent properties which will also affect the ranges of SI values where specific characteristic dissolution profiles may appear. Therefore, sink/nonsink conditions with a clearly defined SI value would be critical for defining an appropriate dissolution method to evaluate formulation performance and product quality of supersaturating formulations.
DO NOT PUSH TOO FAR TOO FAST
The reported effects of rate and degree of supersaturation generation may in part explain the inverse relationship between the in vitro drug release rates and the extent of oral bioavailability as presented in Figs. 2 and 3. A rapid dissolution rate of amorphous fenofibrate in FaSSIF can generate a highly supersaturated drug solution within the first 30 min (Fig. 2c), which inevitably triggers the undesirable crystallization at the early stage of dissolution resulting in a smaller AUC of the kinetic solubility profile as seen in Fig. 2c. If similar uncontrolled nucleation and crystallization occur in the upper GI tract (i.e., in the gastric fluid), the precipitated solids will not be absorbed at the main absorption sites (i.e., duodenum and jejunum), thus significantly reducing the bioavailability when amorphous fenofibrate is orally administered to rats under fasted conditions as presented in Fig. 3. This supports the previous observation that fast dissolution of supersaturating formulations does not always translate into an optimal in vivo performance (12). As shown in the insets of Fig. 6a, b, supersaturating formations with a modest dissolution rate or initial degree of supersaturation can generate a maximum exposure of dissolved drugs in the dissolution medium (i.e., maximum AUC) which are expected to prolong the supersaturated state. Whether this optimum AUC from the kinetic solubility profile translates to optimal oral absorption needs to be further established. Given the above evidence, if a poorly water-soluble drug formulated in supersaturating drug delivery systems is expected to exhibit in vivo dissolution/precipitation kinetics similar to the dissolution profiles presented in Fig. 2c, a gradual or intermediate rate of drug release from ASDs would be more desirable than a rapid “dose-dumping” which creates an instantaneous supersaturation followed by a sharp decline in drug concentration as a result of nucleation and crystallization (31). Hence, the effects of supersaturation generation rate and anticipated degree of supersaturation in vivo should be carefully considered in designing an optimal oral dosage form of supersaturating formulations in order to achieve an appropriate level of sustained solubility enhancement for poorly water-soluble drugs.
THE “PHANTOM” SOLUBILITY OF AMORPHOUS PHARMACEUTICALS
The effect of supersaturation generation rate also has direct implications on the prediction and measurement of solubility advantages of amorphous pharmaceuticals based on the generation of kinetic solubility profiles (27). In previous attempts of estimating the solubility advantages of amorphous solids, there usually exists a large discrepancy between the measured values and those predicted from various estimations of Gibbs free energy difference (32,33). Prior to addressing the presented challenge, it is important to clarify the distinction between the equilibrium solubility (i.e., a thermodynamic property) and the non-equilibrium kinetic solubility (i.e., a kinetic property). The equilibrium solubility of a drug is defined as the maximum quantity of that drug which can be completely dissolved under given temperature, pressure, and solvent conditions (e.g., pH and chemical composition). The equilibrium solubility of a drug is determined from the drug concentration in a saturated solution in thermodynamic equilibrium with excess drug solids (i.e., crystalline). Similar to the equilibrium solubility, intrinsic solubility refers to the equilibrium solubility of an ionizable compound (e.g., an acid or base form) at a pH where it is fully un-ionized. On the other hand, the kinetic (metastable) solubility refers to the maximum achievable drug concentration in a supersaturated state (i.e., above the equilibrium solubility) and is typically determined from the maximum of a kinetic solubility profile.
Since a supersaturated solution is in a thermodynamically non-equilibrium state, phase transformation toward an equilibrium state is a thermodynamically favored process, kinetically driven by the free energy difference between the two states. In practice, the concentration range of the observed kinetic solubility profiles usually lies within an operating window between the equilibrium solubility and a threshold (or critical) supersaturation above which rapid uncontrolled precipitation tends to occur, commonly known as a metastable zone (MSZ) in the field of industrial crystallization (34,35). The MSZ in a temperature-composition phase diagram is defined by the area between a binodal curve (i.e., a saturation point outside of which there is no driving force for nucleation) and a spinodal curve (i.e., a condition at which the metastable system becomes unstable, therefore representing the upper limit of MSZ and once crossed, spontaneous phase separation or spinodal decomposition must occur). In this region of the phase diagram, phase separation can take place and is controlled by a kinetic process described by the classical nucleation theory and crystal growth process. Improved oral bioavailability of supersaturating formulations is attributed to the kinetic solubility enhancement within the metastable zone width (MSZW) in a pharmacokinetically relevant timeframe. In this case, the MSZW depends on a number of intrinsic factors such as the drug’s ability to generate supersaturation and its crystallization propensity. Within such a metastable zone, the time evolution of supersaturation is nevertheless a kinetic process in which a system inevitably moves from a non-equilibrium supersaturated state to an equilibrium saturated state by forming a separate solid phase. Since the observed kinetic solubility of non-equilibrium amorphous solids depends on the rate and the degree of supersaturation generation (27,28), available experimental results highlight the underlying difficulty in determining a reproducible kinetic solubility for amorphous pharmaceuticals. A theoretical framework has been proposed to account for the effects of rate and schedule of supersaturation on the MSZW calculation (34). Kinetically, when the supersaturating system moves away from equilibrium at a faster rate (i.e., higher rate of supersaturation generation in Fig. 7a) or to a greater extent (i.e., higher initial degree of supersaturation in Fig. 7b), a higher maximum supersaturation will be reached despite its ephemeral nature. The large discrepancy in the reported kinetic solubility values may well be the result of different rates of supersaturation generation in these different studies. Consequently, the true solubility advantage of amorphous pharmaceuticals cannot be accurately determined in practice.
Supersaturating formulations are a promising approach to improve oral absorption of poorly water-soluble drugs. Ideally, a supersaturated solution generated by the drug product in contact with the GI fluid should be maintained for a sufficiently long period to facilitate absorption before supersaturation-induced precipitation occurs. Pioneering studies have emphasized the importance of an elevated drug release rate from supersaturating formulations in dissolution testing under perfect sink conditions. Consequently, this early concept of enhanced dissolution rate has been, for quite some time, translated into formulation design strategies incorporating amorphous drugs into rapidly dissolving carriers. In the current article, we have attempted to summarize recent studies in order to bridge the gap in understanding the relationship between dissolution and precipitation kinetics of supersaturating formulations. Specifically, an in vitro-in vivo relationship identified from available data shows that an appropriate reduction in dissolution rate of ASD formulations could actually lead to improved oral bioavailability. In addition, both the rate and extent of supersaturation generation have been shown to have a profound impact on the overall evolution of supersaturation of amorphous pharmaceuticals over time. Exceedingly high rate and extent of supersaturation generation may be detrimental to the solubility enhancement and in vivo oral bioavailability of ASD formulations as shown by both in vitro and in vivo data as well as supported by results from modeling and simulation. In addition, physico-relevant dissolution methods need to be adequately defined with regards to the precise magnitude of departure from a perfect sink dissolution condition, for example using a dimensionless Sink Index (SI), in order to properly characterize and interpret the resulting nonsink dissolution profiles for product performance assessment and quality control purpose. Future research should focus on gaining fundamental understanding of the complex in vivo kinetics of dissolution, precipitation, and pharmacokinetic processes (e.g., absorption) of supersaturating formulations in the GI tract in order to benefit the development of supersaturating oral drug products.
This work was supported in part by funding from the Natural Sciences and Engineering Research Council of Canada (RGPIN 06478–14). D. D. Sun was also supported by a University of Toronto Fellowship Award.
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