Combined Effect of Supersaturation Rate and Dose on the Kinetic

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Combined Effect of Supersaturation Rate and Dose on the Kinetic Solubility Profiles of Amorphous Solid Dispersions based on Water-insoluble Poly(2-hydroxyethyl methacrylate) Hydrogels Giovanna C.R.M. Schver, and Ping I. Lee Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00162 • Publication Date (Web): 30 Mar 2018 Downloaded from http://pubs.acs.org on March 30, 2018

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Molecular Pharmaceutics

Combined Effect of Supersaturation Rate and Dose on the Kinetic Solubility Profiles of Amorphous Solid Dispersions based on Waterinsoluble Poly(2-hydroxyethyl methacrylate) Hydrogels Authors: Giovanna C. R. M. Schver, Ping I. Lee*

Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada

* Corresponding author. Department of Pharmaceutical Sciences, University of Toronto, 144 College Street, Toronto, ON M5S 3M2, Canada. Tel.: +1-416-946-0606; Fax: +1-416-978-8511; E-mail address: [email protected] (P.I. Lee)

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Abstract Kinetic solubility profiles of amorphous solid dispersions (ASDs) based on soluble carriers under nonsink dissolution conditions typically exhibit the so-called “spring-and-parachute” concentration-time behavior. On the other hand, the kinetic solubility profiles from ASDs based on insoluble carriers (including hydrogels) are known to show sustained supersaturation during nonsink dissolution through a matrix-regulated diffusion mechanism by which the drug supersaturation is built up gradually and sustained over an extended period without any dissolved polymer as crystallization inhibitor. Despite previous findings demonstrating the interplay between supersaturation rate and total dose on the kinetic solubility profiles of soluble amorphous systems (including ASDs based on dissolution regulated release from soluble polymer carriers), the combined effect of supersaturation rate and dose on the kinetic solubility profiles of ASDs based on diffusion regulated release from water-insoluble carriers has not been investigated previously. Thus, the objective of this study is to examine the impact of total dose and supersaturation generation rate on the resulting kinetic solubility profiles of ASDs based on insoluble hydrogel carriers. We employed a previously established ASD carrier system based on water-insoluble cross-linked poly(2hydroxyethyl methacrylate) (PHEMA) hydrogel beads and two poorly water soluble model drugs: a weakly acidic indomethacin (IND) and a weakly basic posaconazole (PCZ). Our results show clearly for the first time that by using the smallest particle size fraction and at high dose (i.e. above the critical dose), it is indeed possible to significantly shorten the duration of the sustained supersaturation in the kinetic solubility profiles of ASDs based on waterinsoluble hydrogel carriers such that they resemble the “spring-and-parachute” dissolution profiles normally associated with ASDs based on soluble carriers. This generates sufficiently rapid initial supersaturation buildup above the critical supersaturation resulting in a more rapid precipitation. Above this smallest particle size range, the matrix diffusion regulated nonlinear rate of drug release gets slower which results in a more modest rate of supersaturation buildup leading to a maximum supersaturation below the critical supersaturation level without appreciable precipitation. The area under the curve (AUC) values of in vitro kinetic solubility concentration-time profiles were used to correlate the corresponding trend in dissolution enhancement. There is an observed monotonic increase in AUC values with increasing particle size in high dose ASDs based on water-insoluble hydrogel matrix as oppose to previously reported AUC maximum at some intermediate supersaturation rate or dose in soluble amorphous systems. Whereas in the case of low dose ASDs below the critical dose level, crystallization would be negligible leading to a sustained supersaturation with all particle sizes (i.e. eventually reaching the same maximum supersaturation) but with the smallest particle size reaching the maximum supersaturation the fastest. As a result, the smallest particle size yields the largest AUC value in the case of low dose ASDs based on water-insoluble hydrogel matrix. In addition to probing the interplay between the supersaturation generation rate and the total dose in ASDs based on insoluble hydrogel carriers, our results further support the fact that through either increasing the hydrogel particle size or lowering the total dose to achieve a maximum supersaturation still below the critical supersaturation level, it is possible to avoid drug precipitation so as to maintain a sustained supersaturation.

Keywords: Amorphous solid dispersion; Supersaturation rate; Dose effect; Kinetic solubility; Indomethacin; Posaconazole; PHEMA hydrogels.


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Introduction An increasing number of new drug candidates being generated tend to be poorly watersoluble, thus presenting a major challenge in drug development because poor aqueous solubility often leads to low oral bioavailability. To overcome such a challenge, amorphous solid dispersions (ASDs) where poorly water-soluble drugs are molecularly dispersed and stabilized in appropriate polymer carriers have shown great promise in enhancing the kinetic solubility as well as the oral bioavailability of these drugs.1-4 Here, the stabilized amorphous drug generates a transiently supersaturated drug solution upon dissolution, thereby providing an increased diffusional driving force to enhance the oral absorption. The dissolution of ASDs based on water–soluble polymers is typically very rapid, resulting in a surge of drug supersaturation under nonsink dissolution conditions followed by a decline in drug concentration due to associated drug nucleation and crystallization events. This decline in drug concentration can be retarded to different degrees depending on the effectiveness of the dissolved carrier polymer in inhibiting drug precipitation.5-7 Such ASD dissolution profiles are often characterized by a rapid initial buildup of drug supersaturating “spring” coupled with a precipitation retarding “parachute”, thus the so-called “spring-and-parachute” concentration-time behavior.7,8 In this case, the rate of supersaturation generation as well as the interplay between dissolution and precipitation have been shown to be critical in determining the time evolution of kinetic solubility profiles of soluble ASDs.9 In contrast, kinetic solubility profiles of ASDs based on water-insoluble carriers (such as crosslinked hydrogels) are known to display sustained supersaturation during nonsink dissolution via a matrix diffusion-regulated mechanism, by which the nonlinear rate of drug release gives rise to a gradual buildup of drug concentration resulting in a sustained level of supersaturation over an extended period without detectable precipitation, even in the absence of any dissolved polymer acting as crystallization inhibitor.10-12 For ASDs based on erodible polymers (e.g. HPMC), the more gradual drug release arising from a matrix diffusion-regulated mechanism prevents a sudden surge of supersaturation thus avoiding a rapid decline in drug concentration in the de-supersaturation phase.4,9 In this case, the dissolved polymer from the erosion and dissolution of such ASDs can further retard the decline of supersaturation in the dissolution medium. Thus, it is understood that the kinetic solubility profiles of ASDs based on erodible



polymers are intermediate of those based on water-soluble polymers as well as those based on water-insoluble carriers. Recently, our group has shown that whether the ASD carrier is medium-soluble or medium-insoluble determines the mechanism of release of amorphous drugs from ASDs and therefore directly affects the rate of supersaturation generation and the evolution of supersaturation, which in turn impacts the shape of the resulting nonsink dissolution (i.e. kinetic solubility) profiles of ASDs.13 By selecting appropriate carrier polymers that can be switched from soluble to insoluble by simply changing the pH of the dissolution medium, the kinetic solubility profile from the same ASD system was unequivocally shown to transition from a typical “spring-and-parachute” release behavior to one of sustained supersaturation due to the change in drug release mechanism in dissolution medium of a different pH. More recently, our group has investigated the impact of the total dose on the kinetic solubility profiles resulting from the dissolution of soluble amorphous pharmaceutical systems, demonstrating an alternate strategy to modify the maximum supersaturation and the shape of kinetic solubility profiles by changing the total dose level.14 Both the experimental and simulation results obtained there confirmed the combined effect of supersaturation rate and dose on the kinetic solubility profiles of soluble amorphous systems. At high doses (i.e., above the critical dose relating to critical supersaturation; here critical supersaturation is defined as the supersaturation below which no detectable crystals are formed within the observation time), the maximum supersaturation increased with the supersaturation generation rate, whereas at low doses (i.e., below the critical dose), the maximum supersaturation was shown to be only determined by the total dose level and thus independent of the supersaturation generation rate.14 Despite these previous findings demonstrating the interplay between supersaturation rate and total dose on the kinetic solubility profiles of soluble amorphous systems (i.e. based on water-soluble carriers, including water-soluble polymers or water-miscible organic solvents providing a dissolution regulated release), the combined effect of supersaturation rate and dose on the kinetic solubility profiles of ASDs based on diffusion regulated release from waterinsoluble carriers has not been reported previously. Thus, the objective of this study is to examine the impact of total dose and supersaturation generation rate on the resulting kinetic solubility profiles of ASDs based on insoluble hydrogel carriers. Here, we prepared ASDs of two model poorly water-soluble drugs, a weakly acidic indomethacin (IND) and a weakly basic


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posaconazole (PCZ), in cross-linked poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogel beads, a promising class of water-insoluble ASD carriers.11-12 Previously, PHEMA hydrogel beads have been shown to be advantageous as carriers for ASDs as they typically exhibit sustained

supersaturation

during dissolution

as

oppose to

the

spring-and-parachute

concentration-time profiles from ASDs based on soluble polymer carriers.10,15 In the present study, while maintaining a fixed drug loading and total dose, the particle size range of PHEMA beads was systematically reduced in order to evaluate the impact of the corresponding increase in drug release rate on the resulting kinetic solubility profiles. Additionally, while keeping the particle size fraction and drug loading level fixed, the total dose of these ASDs based on waterinsoluble PHEMA beads was varied in order to highlight the importance of the critical dose level (relating to the critical supersaturation) in determining the shape of the resulting kinetic solubility profiles.

Experimental Section Materials. The monomer 2-hydroxyethyl methacrylate 97% (HEMA) and crosslinker ethylene glycol dimethacrylate 98% (EGDMA) were obtained from Sigma–Aldrich Canada and were distilled under vacuum prior to use to remove any monomethyl ether hydroquinone inhibitor. Polymerization initiator azobisisobutyronitrile (AIBN, Vazo 64®) was obtained from DuPont. PHEMA hydrogel beads having crosslinker concentration of 0.66 mol.% were synthesized by a suspension polymerization process based on previously reported protocols16,17. Different stirring speeds (150, 250 and 300 RPM) were employed during the synthesis to obtain hydrogel beads with different particle sizes. The resulting beads were filtered and extracted with ethanol and distilled water mixture (50:50) before being dried and sieved. The model drug indomethacin 99% was purchased from Sigma-Aldrich Canada and posaconazole 98% from ScinoPharm Shanghai Biochemical Technology, Ltd. (Shanghai, China), and used as received.

Selection of model drugs. Indomethacin (IND), a weak acid, and posaconazole (PCZ), a weak base, were selected as model poorly soluble drugs for this study due to their low aqueous solubility and their reasonable solubility in water-miscible organic solvents to be used for the drug loading process. The physical and chemical properties of these two model drugs are summarized in Table 1.



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Table 1. Physical and chemical properties of the model drugs Structure

MW

pKa

Solubility

• 357.79

4.5 • •

Insoluble in Water; Slightly Soluble in Ethanol; Sparingly Soluble in DMSO and DMF.

Indomethacin (IND)

• 700.78

4.0 • • •

Insoluble in Water; Sparingly Soluble in Methanol; Slightly Soluble in Ethanol; Soluble in DMSO.

Posaconazole (PCZ)

Preparation of ASDs in water-insoluble PHEMA beads. To prepare for ASDs of these model drugs (IND and PCZ), PHEMA hydrogel beads (particle size range from

Combined Effect of Supersaturation Rate and Dose on the Kinetic

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