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Effect of seed particles on precipitation of weak base drugs in physiological intestinal conditions Hiroshi Koyama, Masataka Ito, Katsuhide Terada, and Kiyohiko Sugano Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.6b00297 • Publication Date (Web): 24 Jun 2016 Downloaded from http://pubs.acs.org on June 26, 2016
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Effect of seed particles on precipitation of weak base drugs in physiological intestinal
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conditions
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Hiroshi Koyama, Masataka Ito, Katsuhide Terada, Kiyohiko Sugano*
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Department of pharmaceutics, Faculty of Pharmaceutical Sciences, Toho University,
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2-2-1, Miyama, Funabashi, Chiba, 274-8510, Japan
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* Corresponding author. Tel.: +81 47 472 1494; fax: +81 47 472 1337. E-mail address:
[email protected] (K. Sugano).
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Abstract
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The purpose of the present study was to investigate the effect of seed particles on the
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precipitation behavior of weak base drugs in the small intestine. A simple in vitro
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infusion method was used to mimic in vivo processes. Dipyridamole, pioglitazone,
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topiroxostat, chlorpromazine, cinnarizine, and ketoconazole were used as model drugs.
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A drug was dissolved in 0.01 N HCl and infused into a pH 6.5 buffer. The existence of
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seed particles significantly affected the concentration – time profiles of the model drugs
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in the buffer. The maximum concentration was significantly reduced in the presence of
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seed particles (except for cinnarizine). In the case of dipyridamole, pioglitazone, and
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topiroxostat, the precipitants were crystalline from the beginning of precipitation. In
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contrast, the precipitants of ketoconazole, cinnarizine, and chlorpromazine were a
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mixture of amorphous and crystals. In conclusion, the presence of seed particles
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significantly affected the precipitation behavior of weak base drugs.
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Key words: oral absorption, precipitation, seed particle, weak base, gastric pH, crystal,
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amorphous
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1. Introduction
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The oral absorption of a low solubility free base drug depends on the dissolution profile
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in the stomach. The solubility of a free base drug (Sdissolv) in the stomach is higher than
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that in the small intestine. Therefore, the concentration of a drug dissolved in the
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gastrointestinal fluid (Cdissolv) reduces along transitioning from the stomach to the small
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intestine. In the literature, several pH shift infusion studies investigating the
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precipitation behavior of a weak base drug have been reported.1-3 In these studies, a free
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base drug was completely dissolved in an acidic fluid and infused into a neutral buffer,
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assuming that a free base drug completely dissolves in the stomach before transiting to
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the small intestine. However, considering that dissolution and gastric emptying occur in
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parallel,4 some portion of a dose should reach the small intestine before being
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completely dissolved in the stomach. In addition, the dissolution rate of a free base drug
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in the stomach can be slower than expected from the equilibrium solubility. According to
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the Noyes-Whitney equation,5 the intrinsic dissolution rate of a drug depends on the
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solubility at the solid surface. In the case of a weak base drug of a free form, the
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solubility at the solid surface becomes smaller than that of the equilibrium solubility as
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the buffering effect of the dissolving drugs could increase the solid surface pH more
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than 1 pH unit compared to the bulk fluid pH.6 Furthermore, in some cases, the
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solubilization capacity of the gastric fluid would be less than the dose strength, for
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example, albenzazole, aprepitant, posaconazole, and SB705498. In the cases of
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posaconazole and SB705498, it has been suggested that a large amount of the drug
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administered as a free base reaches the small intestine as undissolved particles and
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accelerates the reduction of Cdissolv.3, 7 Therefore, it would be appropriate to assume that
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some portion of a dose reaches the small intestine before being completely dissolved in
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the stomach. The ratio of dissolved and undissolved drug amounts reaching the small
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intestine depends on the solubility and the dissolution rate of a drug in the stomach.
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Once reaching the small intestine, Cdissolv of a weak base drug would decrease as Sdissolv
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deceases in the small intestine. Reduction of Cdissolv is called “precipitation” in this
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article. The mechanism of precipitation should differ depending on the solid form of an
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administered drug, that is, a free form or a salt form. When a weak base drug is
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administered as a free form, Cdissolv is reduced by the (re-)growth of drug particles
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reaching the small intestine. In other words, they work as seed particles for
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precipitation. In contrast, when a weak base drug is administered as a salt form, seed
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particles of a free form must be generated via a nucleation process before precipitation
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of the free form.8 In both cases, the concentration gradient (Cdissolv > Sdissolv) is the
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driving force for particle growth. In the case when administered as a free form, the rate
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of precipitation in the small intestine should depend on the amount of seed particles
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reaching the small intestine. As previously reported for posaconazole and SB705468,
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when a large portion of the administered free drug reaches the small intestine as
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undissolved particle, it would induce the reduction of Cdissolv. However, the effect of a
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small amount of seed particles on the precipitation process in the small intestine has
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not been investigated.
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The purpose of the present study was to investigate the effect of seed particles on the
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precipitation process of weak base drugs in the small intestine. A simple in vitro
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infusion method was used to mimic in vivo processes. The precipitation behavior of
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weak base drugs was investigated in the presence and absence of seed particles.
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2. Materials and methods
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2.1 Materials
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Dipyridamole was purchased from Wako Pure Chemical Industries Co., Ltd. (Osaka,
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Japan). Ketoconazole was purchased from LKT Laboratories, Inc. (MN, USA).
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Cinnarizine was purchased from Sigma-Aldrich (MO, USA). Dipyridamole, ketoconazole
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and cinnarizine were used as received from the supplier. Pioglitazone hydrochloride and
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chlorpromazine hydrochloride were purchased from Tokyo Chemical Industry Co., Ltd.
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(Tokyo, Japan). Pioglitazone free base was prepared by adding aqueous NaOH to
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pioglitazone hydrochloride in ethanol. Chlorpromazine free base was prepared by
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adding aqueous NaOH to chlorpromazine hydrochloride in water. TOPILORIC Tablets
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were purchased from FUJIYAKUHIN Co., Ltd. (Saitama, Japan). Topiroxostat was
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extracted from TOPILORIC Tablets and recrystallized from water. The coarse and fine
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crystals of dipyridamole were prepared by recrystallization from hot ethanol, grinding,
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and sieving (fine: 53 µm passed, course: 300 µm passed, 180 mesh on.).
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2.2 Methods
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2.2.1 Particle characterization
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The scanning electron microscope (SEM) images of seed particles were obtained with
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Keyence VE-7800 (Keyence, Japan). The particle size was measured by laser diffraction
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particle size analysis (Microtrack MT3000, Microtrack) using water as a dispersant.
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The crystal form was determined by powder X-ray diffraction (PXRD)(Bruker D8,
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Bruker, USA). The diffraction patterns were collected for 3 min from 2θ = 3.8º to 26.3º at
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20 ºC (Cu-Kα radiation source, 40 kV, 40 mA).
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2.2.2 Precipitation study
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A weak base drug was dissolved in 0.01 N HCl. The concentration of a drug was set to be
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clinically relevant (dose/ 250 mL) except for chlorpromazine (Table 1). The drug solution
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was then infused into a sodium potassium phosphate buffer (pH 6.5, 10 mL, phosphate
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= 200 mM, prepared from KH2PO4 and Na2HPO4) in a conical flask with four baffles
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(250 mL, Thermo Fisher Scientific, Inc.) at a rate of 2 mL/min. The flask as gently
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shaken by a nutating shaker at 10 rpm with an angle of θ = 20º at 37 ºC (Nutation mixer,
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Fisher Scientific, Inc.). Nutate shaking combines the motions of an orbital shaker and a
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rocker to produce a three dimensional action, providing thorough yet gentle mixing. The
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infusion was terminated at 40 min. The pH of the solution was ca. 6.2 at the end of
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infusion. The solution was filtered through a filter at each time point (hydrophilic PVDF,
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0.45 µm). The first few drops were discarded to avoid filter adsorption. Cdissolv was
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determined by UV spectrometry (Table 1) (SpectraMax 190, Molecular Devices, LLC.).
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The solid form of precipitated particles during the infusion experiment was observed
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with a polarized light microscope (Eclipse, Nikon Corporation). The final solid form at
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the end of experiment was determined by PXRD.
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2.2.3 Equilibrium solubility measurement
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A model drug (free base, 150 mg) was added to a 15 mL centrifuge tube. Ten milliliter of
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200 mM sodium phosphate buffer (pH 6.5) was then added. The sample was vigorously
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shaken at 37 ºC for 4, 24 and 72 hours. The dissolved drug concentration was
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determined as described above.
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Results
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Six weak base drugs were employed in this study (Figure 1, Table 1). Ketoconazole,
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dipyridamole, cinnarizine, and pioglitazone were selected as precipitation in the
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intestine has been suggested to play a significant role in oral drug absorption.9-12
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Chlorpromazine was selected as it was suggested to precipitate as amorphous.13
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Topiroxostat was selected as it possess a low pKa value compared to the other model
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drugs. The range of pKa values of the model drugs was from 3.88 to 9.50.
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Figure 2 shows the SEM images of the model drugs (free base). All seed particles were
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crystalline with the particle size less than 50 µm. The d50 values were shown in Table 1.
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The d50 values of dipyridamole, cinnarizine and chlorpromazine were about 45 µm. The
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d50 values of ketoconazole, topiroxostat and pioglitazone were 10 to 20 µm.
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Dipyridamole, cinnarizine, chlorpromazine and ketoconazole showed a monomodal
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particle size distribution, whereas topiroxostat and pioglitazone showed a bimodal
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particle size distribution. The peak positions were 8 µm and 25 µm for topiroxostat, and
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1.5 µm and 30 µm for pioglitazone.
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