Article pubs.acs.org/molecularpharmaceutics
Fumaric Acid Microenvironment Tablet Formulation and Process Development for Crystalline Cenicriviroc Mesylate, a BCS IV Compound Mark M. Menning* and Sean M. Dalziel Technical Operations, Tobira Therapeutics, Inc., South San Francisco, California 94080, United States ABSTRACT: Cenicriviroc mesylate (CVC) is a potent dual antagonist of C-C chemokine receptor type 5 (CCR5) and C-C chemokine receptor type 2 (CCR2) in phase 2b development as an entry inhibitor for HIV-1 infection treatment.1,2 CVC is a weak base exhibiting BCS IV characteristics with a highly pH dependent solubility profile (>100 mg/mL for pH < 2 and 4) and low Caco-2 cell line permeability. Previous tablet formulations of CVC, including spray-dried dispersion and a wet granulation with citric acid, had been found unacceptable for commercial use due to chemical and physical instability or unacceptably high excipient loading precluding fixed-dose combinability. A high drug loading, 26% (w/w), acidic microenvironment tablet formulation with fumaric acid solubilizer (1:1 CVC/fumaric acid) and a dry granulation process was developed iteratively through a sequence of prototypes characterized by beagle dog absorption studies, focused beam reflectance measurement (FBRM), dynamic vapor sorption (DVS), and accelerated stability testing. The fumaric acid based dry granulated product demonstrated a mean bioavailability comparable to an oral solution dose in a dog model. Stability and moisture sensitivity of the formulation were improved via the dry granulation process technique and the use of fumaric acid. It is hypothesized that the observed slow dissolution kinetics of fumaric acid prolongs an acidic microenvironment around the agglomerated CVC crystals and excipients leading to increased CVC dissolution and thereby absorption. The fumaric acid formulation also demonstrated absorption resilience to gastric pH extremes in a dog model. This optimized formulation and process enables CVC to be a viable candidate for current HIV treatment paradigms of single once daily fixed-dose combination products. KEYWORDS: cenicriviroc, mesylate salt, solubilization, microenvironment pH, dry granulation, fumaric acid, citric acid, focused beam reflectance measurement (FBRM), BCS IV, HIV, CCR5, CCR2
■
INTRODUCTION
A high proportion of HIV patients also take either proton pump inhibitors (PPI) or H2-receptor antagonists (H2RA) for the treatment of gastresophageal reflux disease.8 Increases in stomach pH can affect the absorption of weakly basic drugs such as the HIV protease inhibitor atazanavir and the nonnucleoside reverse transcriptase inhibitor rilpivirine.9,10 Drug− drug interactions involving modification of the gastric pH require careful management of the dosing window of the PPI or H2RA relative to the antiretroviral dosing. Formulations with pH-independent absorption characteristics are desirable. The oral bioavailability of a drug substance in a tablet formulation is generally driven by solubility, permeability, and metabolism. The rate of drug dissolution is a critical parameter to optimize for a drug substance with low solubility, such as CVC, over a range of physiologically relevant pH (1−8). The
Cenicriviroc mesylate (CVC) is a novel, potent dual C-C chemokine receptor type 5 (CCR5) and C-C chemokine receptor type 2 (CCR2) antagonist currently in phase 2b clinical development for the treatment of HIV-1 infection.1,2 CVC is a weak base exhibiting BCS IV characteristics with a highly pH dependent solubility profile and low Caco-2 cell line permeability. This paper describes the process of reformulating CVC into an acidic microenvironment single tablet of moderate size and weight while achieving improvements in bioavailability, stability, and ease of manufacturing. The current treatment guidelines for HIV infection recommend combination antiretroviral therapy in all patients regardless of HIV-1 RNA levels or CD4+ counts.3 The treatment of HIV has evolved substantially to a simple paradigm of complete regimens of potent and durable antiviral agents available in single once daily fixed-dose combination tablets, resulting in improved patient compliance and outcomes. 3−7 Where permissible, new antiretroviral (ARV) drugs under development are formulated with minimal excipient load and tablet mass to optimize opportunities for product diversification as a single fixed-dose combination tablet. © XXXX American Chemical Society
Special Issue: Impact of Physical Chemical Drug-Drug Interactions from Drug Discovery to Clinic Received: May 16, 2013 Revised: August 7, 2013 Accepted: August 13, 2013
A
dx.doi.org/10.1021/mp400286s | Mol. Pharmaceutics XXXX, XXX, XXX−XXX
Molecular Pharmaceutics
Article
Noyes−Whitney equation (eq 1) establishes the relationship between the dissolution rate and the solubility of the drug in the diffusion layer and the solubility of the compound in the surrounding medium.11 dC D·S = = (Cs − C) dt h
(1)
where D = diffusion coefficient, S = surface area of solid, h = diffusion layer thickness, Cs = concentration of saturated solution at surface, and C = bulk concentration. Several established methods enhance equilibrium drug solubility or the kinetic rate of dissolution to increase bioavailability. Common techniques harnessing the principles of the Noyes−Whitney equation include salt formation to increase intrinsic solubility of the active ingredient solid form,12 particle size reduction to increase surface area for mass transfer, alteration of the aqueous contact angle and wettability using surfactants, lipid cosolvents, and amorphous spray-dried dispersions to reduce the heat of solution of the dissolving phase. The pH profile of the diffusion layer affects the dissolution rate for weakly acidic and basic drugs. Introducing an acidifying or basifying excipient to increase solubility can also increase the concentration of the drug at the excipient and drug particle interface. Adjusting the pH at the drug interface will change the boundary layer thickness and the rate of dissolution. The apparent thickness of the stagnant layer can be reduced when the drug dissolves into a reactive medium modulated by the interfacial pH at the boundary layer. The effective thickness is therefore controlled at the point of contact between the acid or base particles and the drug substance particles. Organic and inorganic acids and bases have been used to modify the microenvironment pH in solid dosage forms.13,14 Tartaric acid has been explored as a functional excipient to buffer gastric pH fluctuations.15 Citric, fumaric, malic, succinic, and tartaric acids have been explored to control the microenvironment pH in modified release formulations to modulate pH-dependent release rate of the functional polymer,16 or to achieve pH-independent dissolution of a weakly basic drug from polymeric matrices.17,18 An alternate approach is reacidification of the macroenvironment via coadministration of high dose betaine acid salts.19 While this can effectively reacidify the bulk gastric pH countering the effects of acid reducing agents, the mass of acidifier needed to affect the stomach pH is not amenable to use in limited size single tablet fixed dose combination products for HIV infection treatment. The goals of this work are (1) to formulate crystalline CVC in an acidic microenvironment single, once daily tablet of comparable or higher bioavailability and physical and chemical stability than previous formulations of CVC (amorphous spraydried dispersion, lipid, surfactant, and citric acid based multitablet, once daily products), (2) to minimize the excipient load and total tablet mass as a lead toward future fixed-dose combination product development with other ARV agents, and (3) to apply formulation approaches to minimize the impact of gastric pH modifying coadministered drugs or antacids.
Figure 1. Cenicriviroc mesylate chemical structure.
host cells by HIV-1. CVC also has an antagonistic effect on CCR2, a chemokine receptor associated with anti-inflammatory pathways. CVC has nanomolar potency against CCR5 tropic virus and has a half-life greater than 30 h in humans that is suitable for once-daily dosing. CVC is a polyprotic weak base. The first pKa is 4.3 at the ternary nitrogen in the benzazocine ring. The second pKa is 6.2 at the N-3 position on the imidazole group. CVC is hydrophobic with a log P > 3. Aside from the weak base nature of CVC, the remaining portion of the compound is relatively nonpolar. CVC is soluble in alcohols and some other organic solvents. In water, there is a steep rise in the solubility of the compound below pH 3, approximately two log units below the lowest pKa, once the compound is fully protonated. CVC is chemically stable in the solid state. In solution, the predominant degradation pathways include dealkylation of the butyl groups, oxidation of the sulfoxide to form a sulfone, and hydrolysis of the amide bond. A monomesylate salt was selected as the drug substance solid form because it yields a highly stable nonhygroscopic crystalline solid with a high melting point at 153 °C. The dimesylate form is a less stable, hygroscopic crystalline form. The mesylate counterion is also advantageous because it is a strong acid with a low molecular weight.22 Additionally, the apparent permeability (Papp) of CVC is less than 1 × 10−6 cm/s, making it a low permeability, low solubility, BCS IV compound.23 Formulation interventions were designed to increase the solubility once administered to transition its biopharmaceutical behavior to resemble a BCS III compound.
■
MATERIALS AND METHODS Cenicriviroc Mesylate. The three distinct lots of CVC used in this work exhibited the same highly crystalline monomesylate solid form and were similar in assay and purity (>99%). The primary particles were approximately 1 to 10 μm in diameter as determined by scanning electron microscopy (Figure 2) and are consistent with the particle size distributions measured by a laser diffraction technique. Excipients. All ingredients were compendial grade commonly used for pharmaceutical tablet manufacture. Ingredients include citric acid (anhydrous powder; JT Baker Avantor, Center Valley, PA), crospovidone (Polyplasdone XL; Ashland, Covington, KY), croscarmellose sodium (Ac-Di-Sol; FMC Corporation, Philadelphia, PA), fumaric acid (Granular FF; Polynt Scanzorosciate, Bergamo, Italy), hydroxypropyl cellulose (HPC-L; Nippon Soda, Tokyo, Japan), hypromellose acetate succinate (HPMC-AS, AQOAT; Shin-Etsu, Tokyo, Japan), mannitol (Pearlitol C; Roquette America, Geneva, IL), microcrystalline cellulose (Avicel PH101 and Avicel PH102; FMC Corporation, Philadelphia, PA), magnesium stearate (Hyqual 5712; Covidien Mallinckrodt, Mansfield, MA), silicon
■
CENICRIVIROC MESYLATE The chemical structure of CVC, (5E)-8-[4-(2-butoxyethoxy)phenyl]-1-(2-methylpropyl)-N-[4-[(S)-(3-propylimidazol-4-yl)methylsulfinyl]phenyl]-3, 4-dihydro-2H-1-benzazocine-5-carboxamide; methanesulfonic acid, is presented in Figure 1.20,21 CVC blocks the use of CCR5 as a coreceptor for entry into B
dx.doi.org/10.1021/mp400286s | Mol. Pharmaceutics XXXX, XXX, XXX−XXX
Molecular Pharmaceutics
Article
dioxide, and acid solubilizer (citric acid, fumaric acid, maleic acid, or sodium bisulfate) and tumble blended. Magnesium stearate was added, and the mixture was blended. Spray-Dried Dispersion. A typical 19 kg batch of spraydried intermediate was prepared as follows: A 10% (w/w) solution of CVC and hypromellose-AS (HPMC-AS) at 1:3 CVC/polymer was prepared by dissolving CVC and hypromellose in methanol. The solution was spray dried in a GEA-Niro model PSD-2 (Columbia, MD) spray drier. The resulting particles were collected in a cyclone collection container. Secondary tray drying of the spray-dried intermediate powder was performed to ensure complete removal of methanol. The spray-dried intermediate was blended in a tumble blender with microcrystalline cellulose, mannitol, silicon dioxide, sodium lauryl sulfate, and croscarmellose sodium. Magnesium stearate was added and blended again. The resulting mixture was dry granulated with a roller compactor (Gerteis Minipactor, Jona, Switzerland) at a normalized roll force of 6.5 kN/cm with an integrated oscillating mill. The granules were blended with silicon dioxide and magnesium stearate. CVC tablets (50 mg) were compressed using 7/16 in round standard concave tooling to the target hardness. CVC tablets for dog studies (25 mg) were prepared by splitting 50 mg strength tablets with a razor blade and accurately weighing each half. Dry Granulation. A typical 400 g batch size of dry granulated CVC powder blend was prepared as follows: CVC, fumaric acid, the intragranular portion of microcrystalline cellulose, and croscarmellose sodium were transferred into a tumble blender and blended. The intragranular portion of the magnesium stearate was then added and blended. The resulting powder blend was dry granulated using a roller compactor (TFC-LAB Micro, Freund-Vector, Tokyo, Japan) at a roll pressure of 500 psi and then milled. The granules were then blended with microcrystalline cellulose and croscarmellose sodium. Magnesium stearate was then added and blended. CVC tablets (150 mg) were compressed to target hardness using a 16 × 8 mm capsule-shaped tooling. CVC tablets for dog studies (25 mg) were prepared using 1/4 in. round standard concave tooling. pH Solubility. The aqueous solubility of CVC mesylate was determined throughout the pH range of 2.0 to 8.0 using Britton-Robinson buffers: 0.04 M phosphoric acid, 0.04 M acetic acid, and 0.04 M boric acid adjusted with 0.2 M NaOH solution, as necessary, to obtain the desired pH.24 A pH 1.0 solution was prepared using hydrochloric acid. The suspensions were shaken for 30 s at 5 min intervals for 30 min at 20 °C and then filtered through a 0.45 μm filter. After the pH value was measured, the filtrate was diluted and injected into an HPLC system for quantitative analysis. Dog Pharmacokinetics. The absolute bioavailability of various prototype formulations of CVC were compared in fasted male beagle dogs at WuXi Biosciences (Shanghai, China).25 The corresponding CVC plasma concentrations were studied in the same five beagle dogs (mass approximately 8−10 kg) fasted unpretreated, pentagastrin-pretreated, and famotidine-pretreated. For pentagastrin pretreatment, each animal received intramuscular administration of pentagastrin (0.12 mg/mL, 0.05 mL/kg) approximately 30 min before dosing CVC. For famotidinde pretreatment, each animal received an intravenous (iv) bolus administration of famotidine (10 mg/ mL, 0.05 mL/kg) approximately 90 min before dosing. The fasted unpretreated condition was selected for formulation
Figure 2. Scanning electron microscope image of cenicriviroc mesylate.
dioxide (Cab-O-Sil M5P; Cabot, Boston, MA), silicon dioxide (Aerosil 200; Evonik, Essen, Germany), sodium lauryl sulfate (Stepanol WA-100; Stepan Company, Northfield, IL), and talc (Luzenac Pharma; Imerys Talc, Paris, France). Tablets Manufactured by Fluid-Bed Granulation. A typical 3 kg final blend batch size of CVC was prepared as follows using a Freund-Vector model FLM3 (Freund-Vector Corporation, Tokyo, Japan) fluid-bed processor. CVC, citric acid, silicon dioxide, mannitol, and microcrystalline cellulose were added to the fluid bed and fluidized to blend and equilibrate the powder-bed temperature. The binder solution containing an aqueous solution of 7.5% (w/w) hydroxypropyl cellulose was atomized at 30 psi and added to the powder bed over 45 to 65 min while the product temperature was maintained between 40 and 45 °C. Following the spray of the binder solution, the wet granules were dried. A final moisture content end point of less than 2.0% by loss on drying was determined using a moisture analyzer/balance (MettlerToledo, Columbus, OH, USA) at 105 °C. The dried granules were passed through a conical mill. The milled granules were then blended in a V-shaped tumble blender with extragranular excipients, croscarmellose sodium and talc, for the initial blending, followed by blending with magnesium stearate. Tablets were compressed to 600 mg mass using 0.3346 × 0.5315 in capsule-shaped tooling. High-Shear Wet Granulation. A typical 200 g final blend batch size of CVC was prepared as follows: CVC, croscarmellose sodium, and mannitol were added to a 1 L granulator bowl (Key International, Cranbury, NJ) and blended with an impeller speed of 100 rpm (0.7 m/s tip speed) for 10 min. An aqueous 10% (w/w) hydroxypropyl cellulose solution was poured directly onto the powder bed over approximately 2−3 min with an impeller speed of 100 rpm. The mixture was then wet massed at the same impeller speed for 1 min to form uniform granules. The wet granules were tray dried in an oven at 60 °C to obtain a loss on drying less than 2.0% (w/w). The resulting granules were sieved through a 40 mesh screen. The granules were blended with croscarmellose sodium, silicon C
dx.doi.org/10.1021/mp400286s | Mol. Pharmaceutics XXXX, XXX, XXX−XXX
Molecular Pharmaceutics
Article
prototype comparisons because the gastric pH condition was more discriminating than when pretreated with pentagastrin. Doses of 25 mg of CVC were evaluated in each dog with samples of gastric fluid taken before and after dose to confirm pH. Typical pH ranges measured for gastric fluid predose were as follows: (1) pentagastrin-pretreated pH 0.7−1.5; (2) unpretreated pH 1.5−3.0; (3) famotidine-pretreated pH 6.0− 8.0. Since CVC is a yellow colored active ingredient, a useful visual indication of CVC dissolution was possible from the yellow color of solution from the gastric pH samples withdrawn after tablet administration. The 25 mg dose was a 6-fold reduction of the highest phase 2a human dose of 150 mg based on the approximate ratio of human to dog stomach fluid volumes and total body weights. The absolute bioavailability (% F) was calculated using the results of an iv administered control. Blood samples for bioanalytical analysis were taken at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, and 24 h time points. Other control groups evaluated an unformulated CVC powder in a hard gelatin capsule and an oral solution containing CVC at 2.5 mg/ mL (freebase equivalent) in a 10% ethanol, 60% PEG400, and 30% purified water solution with a dose volume of 10 mL. This dog pharmacokinetic technique was used iteratively to optimize the tablet formulation composition and method of manufacture due to reserving the same five dogs and a rapid turnaround of bioanalytical results, typically within one week from dosing. Dynamic Vapor Sorption. Hygroscopicity of CVC at 25 °C was evaluated by dynamic vapor sorption (DVS) using an automated vapor sorption balance, Advantage DVS-1 (Surface Measurement Systems, Middlesex, United Kingdom). Approximately 3−5 mg of material was placed directly into the sample cup. The first step of the DVS experiment involved drying the material from 40% relative humidity (RH) down to 0% RH until a constant weight was achieved. The weight of the sample after equilibration at 0% RH was taken as the starting experimental values for the dry material. After equilibration, the RH was increased in increments of 5% up to 90%, and the water sorption was monitored. For desorption, the relative humidity was decreased in a similar manner to accomplish a sorption/desorption cycle. Focused Beam Reflectance Measurement. Focused beam reflectance measurement (FBRM) is a particle characterization probe (Mettler-Toledo AutoChem Inc., Columbia, MD) that operates by collating the chord length particle size distribution data from all particles passing through the focal point of laser optics rotating at 2 m/s in a given measurement duration (Figure 3).26 FBRM measurements were performed by APC (Dublin, Ireland). Tablet disintegration was monitored by introducing tablets into 90 mL of purified water using a Mettler-Toledo mixing chamber held at 37 °C with an upward pumping four blade impeller at 250 rpm. The total particle counts were monitored for each tablet formulation over time. Acid dissolution experiments were performed by adding 200 mg of each acid to 90 mL of purified water and monitoring the disappearance of particles undergoing dissolution. Data was analyzed by collecting and averaging over 2, 10, and 30 s measurement intervals. Adipic, citric, fumaric, maleic, sodium bisulfate, succinic, and tartaric acids were compared by this technique at either 25 or 37 °C. Accelerated Stability Testing. Samples were stored in induction sealed bottles with 30 tablets and 3 g of desiccant at 40 °C/75% RH. The assay, impurities, and degradation products of the CVC tablets were determined using a stability indicating HPLC method. Composite samples of tablets were
Figure 3. Operating principle behind FBRM probe and the generation of a chord length distribution. A laser is focused to a fine spot at the sapphire window interface, and individual particle structures backscatter the laser light back to the probe. Pulses of backscattered light are detected by the probe and translated into chord lengths based on the calculation of the scan speed (velocity) multiplied by the pulse width (time). Reprinted with permission from Mettler-Toledo AutoChem Inc.’s product information brochure. Copyright 2009 Mettler-Toledo AutoChem Inc.
dissolved and diluted to final concentrations using a mixture of pH 4 acetate buffer and acetonitrile. The assay of CVC was determined using HPLC at a wavelength of 293 nm with area normalization and an external reference standard. Dissolution. Dissolution testing was performed on the CVC tablets using a United States Pharmacopoeia (USP) type II dissolution apparatus at a paddle speed of 50 rpm with 900 mL of 0.1% cetyl trimethylammonium bromide (CTAB) in 0.1 N HCl maintained at 37 °C. The amount of CVC dissolved at 60 min was recorded.
■
RESULTS AND DISCUSSION Initial Formulation Concepts. The pH solubility profile of CVC is shown in Figure 4. The steep change in solubility at pH
Figure 4. CVC pH solubility profile in buffered water.
values approximately 1.5−2.0 units lower than the lowest pKa of 4.3 presents a region of interest. At this low pH, the molecule is doubly protonated, resulting in a rapid rise to greater than 100 mg/mL solubility. The exceedingly high solubility that is achievable in such acidic conditions explains why CVC is prone to gelation when in contact with water. Strong counterion acids, such as monomethansulfonic acid, are useful for salt formation to improve the aqueous solubility of poorly soluble drug D
dx.doi.org/10.1021/mp400286s | Mol. Pharmaceutics XXXX, XXX, XXX−XXX
Molecular Pharmaceutics
Article
often a preferred methodology for increasing solubility of poorly soluble drug substances. The spray-dried formulation was developed at 1:3 CVC/HPMC-AS polymer with the tablet formulation composition summarized in Table 3. To further aid the wettability, 2.0% sodium lauryl sulfate was added to the extragranular portion of the tablet.
substances. However, high solubility in this pH region of the CVC salt results in dissolution and the creation of a gel that may reduce the stability and oral bioavailability.27 Decreasing the pH at the CVC excipient particle interface may increase the rate and extent of dissolution of CVC. Citric acid was previously chosen as the solubilizer to aid with oral bioavailability and decrease the microenvironment pH during dissolution for phase 1 and phase 2a clinical study formulations. The granulation was manufactured by a spray granulated fluid-bed process with citric acid added at 75 mg intragranularly with a drug loading of 25 mg of CVC per tablet as shown in Table 1.
Table 3. Spray-Dried Dispersion Tablet Formulation Composition
Table 1. Phase 1 and Phase 2a Clinical Tablet Formulation Composition Manufactured by Fluid-Bed Wet Granulation Process
a
components
concn (% w/w)
unit formula (mg/unit)
cenicriviroc mesylate mannitol microcrystalline cellulose silicon dioxide citric acid croscarmellose sodium hydroxypropyl cellulose talc magnesium stearate total
4.74 56.93 13.33 2.00 12.50 5.00 2.00 2.00 1.50 100.0
28.45a 341.55 80.00 12.00 75.00 30.00 12.00 12.00 9.00 600.0
Accelerated stability testing of the citric acid containing formulation of CVC tablets at 40 °C/75% RH displayed a significant reduction in dissolution after three to six months of stability testing. The percent CVC released decreased from >90% at 60 min to only 16% release at the 12 week time point as shown in Table 2. In addition to the decrease in dissolution Table 2. Accelerated Stability of Wet Granulated 25 mg of CVC Tablets Containing Citric Acid
initial release 4 weeks 12 weeks
CVC dissolved at 60 min (%)
total impurities and degradation products
91
0.6
92 16
0.8 2.6
concn (% w/w)
unit formula (mg/unit)
cenicriviroc mesylate hypromellose acetate succinate sodium lauryl sulfate croscarmellose sodium microcrystalline cellulose mannitol silicon dioxide magnesium stearate total
8.33 25.00 2.00 6.00 27.83 27.83 1.00 2.00 100.0
50.00 150.00 12.00 36.00 167.00 167.00 6.00 12.00 600.0
The spray-dried dispersion formulation achieved acceptable physical and chemical stability and adequate oral bioavailability for a phase 2b dose optimization study.2 The phase 2b study required two tablets to supply 100 mg of CVC and four tablets to supply 200 mg daily doses of CVC. This multiunit regimen can introduce patient adherence issues and may be more cumbersome to manage than a single tablet regimen. The low CVC concentration at 8% (w/w) increased the excipient burden and increased the challenge to develop a fixed-dose combination product with CVC using this spray-dried formulation. Phase 3 clinical trials for HIV infections increasingly use single tablet fixed-dose combinations to improve patient compliance.29 Screening of Additional Pharmaceutically Acceptable Acids. Several acids acceptable for use in pharmaceutical products as excipients are shown in Table 4.12,28 Many of the acids are polyprotic and weak carboxylic or mineral acids. Citric, fumaric, maleic, and tartaric all have been used in approved oral solid dosage products.30 As summarized in the table, with the exception of adipic and fumaric acids, all of the solid forms are hygroscopic, which commonly presents stability and processing difficulties. To screen the functional role of some of these acids in CVC prototype tablet formulations, a common high-shear wet granulation was used with a fixed intragranular composition of CVC and nonacidic excipients, listed in Table 5. Prototype tablets were prepared by blending each acid extragranularly and compressing into tablets. The acid to drug mass ratio was kept constant at 1.5:1 in this study. The four prototypes prepared with citric, fumaric, maleic, and sodium bisulfate acidic excipients were tested for absolute bioavailability via oral administration compared to an iv dosed control in male beagle dogs under fasted state conditions (Figure 5). The rank order of mean exposure (% F) for the various acids was highest for fumaric acid, then citric acid, maleic acid, and lowest for sodium bisulfate. For reference, an unformulated CVC powder in a hard gelatin capsule in fasted state beagle dogs demonstrated an absolute bioavailability of 6.4%. This result was surprising because the acids with the highest acidic strength, maleic and sodium bisulfate, had lower exposure than citric and fumaric acid. Fumaric acid has the lowest aqueous solubility of all of the acids.
Equivalent to 25 mg of cenicriviroc freebase.
time point
components
rate, there was an increase in the sulfone degradation product related to water mediated oxidation reactions. Total impurities and degradants increased by 2.0% from the initial release sample. Citric acid is known to absorb significant amounts of water especially at relative humidities greater than 75% and can also deliquesce at high humidity values.28 The wet granulation formulation containing citric acid, even when stored with desiccant, was not chemically and physically stable and therefore not viable for development beyond phase 2a clinical studies. Spray-Dried Dispersion Formulation. Given the significant physical and chemical stability issues observed during accelerated stability testing with CVC tablets containing citric acid, a formulation based on an amorphous spray-dried dispersion was subsequently developed to encapsulate CVC in an HPMC-AS polymer matrix. Spray-dried dispersions are E
dx.doi.org/10.1021/mp400286s | Mol. Pharmaceutics XXXX, XXX, XXX−XXX
Molecular Pharmaceutics
Article
Table 4. Summary of physicochemical properties of pharmaceutically acceptable/GRAS acids acid dissociation constant12 acid
pKa1
pKa2
acetic adipic
4.756 4.44
5.44
citric fumaric
3.128 3.03
4.761 4.38
lactic maleic acid malic phosphoric sodium bisulfate succinic tartaric
3.86 1.92 3.459 1.96 1.99
6.23 5.097 7.12
4.207 3.02
5.635 4.36
pKa3
6.396
12.32
mol wt12
solubility in water at 20 °C27
60.05 146.14
miscible sparingly soluble
0.26% (syrup) no oral products
192.13 116.08
very soluble slightly soluble
839.63 mg (tablet) 200 mg (powder)
90.08 116.08 134.09 98.00 120.06
miscible freely soluble freely soluble miscible freely soluble
44 mg (capsule) 4 mg (tablet) 31.5% (solution) 2.975 mg (tablet) 0.095% (concentrate)
liquid nonhygroscopic solid hygroscopic solid nonhygroscopic solid hygroscopic liquid hygroscopic solid hygroscopic solid liquid hygroscopic solid
118.09 150.09
slightly soluble freely soluble
65.1 mg (tablet) 215.1 mg (capsule)
hygroscopic solid hygroscopic solid
unit formula (mg/unit)
cenicriviroc mesylate mannitol hydroxypropyl cellulose croscarmellose sodium citric acid fumaric acid maleic acid sodium bisulfate silicon dioxide magnesium stearate total a
citric acid
fumaric acid
maleic acid
sodium bisulfate
28.45a 7.88 2.62
28.45a 7.88 2.62
28.45a 7.88 2.62
28.45a 7.88 2.62
3.50 43.75
3.50
3.50
3.50
Table 6. Dissolution Times of Acid Excipients Alone in Water Measured by FBRM
43.75 43.75 0.43 0.88 87.5
0.43 0.88 87.5
0.43 0.88 87.5
handling properties27
residence time, because of slow dissolution kinetics, may increase the drug and acid interaction for solubilization. Fumaric acid also has the advantages of having a low molecular weight, requiring a low mass quantity for use, and it is a nonhygroscopic diprotic acid that can be readily used in conventional drug product processes. Solubility and dissolution rate of the acid can affect the drug product performance. Using fumaric acid in an immediate release CVC tablet is best guided by assessing the intrinsic dissolution rate of fumaric acid. Table 6 summarizes the dissolution rates of the various acids alone in water using FBRM. The only acid that had a slow
Table 5. Tablet Formulation Compositions (Wet Granulated) to Screen Citric, Fumaric, Maleic, and Sodium Bisulfate Acids
components
max concn in an FDA approved oral drug product (dosage form)29
43.75 0.43 0.88 87.5
dissolution time (s)
Equivalent to 25 mg of cenicriviroc freebase.
acid
25 °C
37 °C
adipic citric fumaric maleic sodium bisulfate succinic tartaric
68 6 312 4 26 46 6
32
