Expedited Development of Diphenhydramine Orally Disintegrating

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Expedited development of diphenhydramine orally disintegrating tablet through integrated crystal and particle engineering Chenguang Wang, Shenye Hu, and Changquan Calvin Sun Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.7b00423 • Publication Date (Web): 21 Aug 2017 Downloaded from http://pubs.acs.org on August 22, 2017

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Molecular Pharmaceutics

Expedited development of diphenhydramine orally disintegrating tablet through integrated crystal and particle engineering

Chenguang Wang, Shenye Hu, and Changquan Calvin Sun*

Pharmaceutical Materials Science and Engineering Laboratory, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA

*Corresponding author Changquan Calvin Sun, Ph.D. 9-127B Weaver-Densford Hall 308 Harvard Street S.E. Minneapolis, MN 55455 Email: [email protected] Tel: 612-624-3722 Fax: 612-626-2125

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Abstract To develop a palatable direct compression (DC) orally disintegrating tablet (ODT) product of a bitter drug, diphenhydramine (DPH), using an integrated crystal and particle engineering formulation development approach. A DPH salt with a sweetener, acesulfame (Acs), DPH-Acs, was synthesized and its solid state properties were comprehensively characterized.

Tablet formulation composition and

compaction parameters were optimized by employing material sparing techniques. In vivo disintegration time, bitterness, and grittiness of the final ODT product, were evaluated by a taste panel. Physical stability of the ODT tablets was assessed to identify appropriate storage conditions. Phase-pure DPH-Acs exhibited significantly better tabletability and palatability than DPH-HCl.

A DC formulation was

designed and optimized to obtain a new ODT product with good manufacturability and excellent product characteristics, including faster in vivo disintegration, and acceptable bitterness and grittiness. The entire development activities required only 15 g of DPH and a period of two months. A new ODT product of DPH with excellent pharmaceutical properties was successfully developed in a short time. This example shows that integrated crystal and particle engineering is an effective approach for developing high quality ODT products using the DC process. KEY WORDS：：orally disintegrating tablet, sweet salt, formulation development, direct compression,


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Introduction The successful development of a new molecular entity into a drug product, from discovery to regulatory approval, is expensive, partially due to the high attrition rate.1 Life cycle management strategies pursued by pharmaceutical companies to extend their product portfolio broadly fall in two categories, a) seeking new indications of an approved drug,2 and b) developing a new product with improved pharmaceutical performance over the existing ones. In the latter case, common approaches include enantiomer switch,3, 4 prodrug,5 novel solid form,6 reformulation with more convenient dosing regimen, and drug combinations.7 Such new drug products usually have one or more of the following advantages, including potency, efficacy, safety, or patient compliance, compared to the corresponding commercial product. These changes can extend patent protection of the drug.8 One well-known example of successful life cycle management is diclofenac, which was initially launched at 1973 under the trade name Voltaren and remained in the market for over 30 years. Its commercial value has been significantly enhanced by using new salts, reformulation, new drug delivery systems, and fixed dose combination products.9 Another case is atorvastatin, which was originally discovered in 1980s and introduced to the market in 1996 under the brand name Lipitor.

The significant commercial value was

safeguarded by patenting new solid forms of its calcium salt and formulations.10 Diphenhydramine (DPH) is a first-generation H-receptor antagonist (Figure 1a) commonly used as an over-the-counter medication to treat allergies and aid sleep.11 It was first included in United States Pharmacopeia (USP) in 1982. DPH is a weak base (pKa = 8.76) that is freely soluble in water.12 Various dosage forms of DPH are commercially available, such as syrup, suspension, solution, capsule, immediate release tablet, liquid filled capsule, soft gel, chewable tablet, and orally disintegration tablet (ODT). In contrast to the flurry of activities in 3 ACS Paragon Plus Environment


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formulation development, its solid form landscape has not been well explored. Currently, only the hydrochloride, tannate, and citrate salts are used in commercial products of DPH. Among the commercial products of DPH, ODT has a unique role. In addition to the usual advantages of tablets, such as greater stability, manufacturing efficiency, and economy,

13

ODTs also bring convenience to dysphagia patients, such as children and the elderly, or when access to water is limited. Moreover, the high degree of vascularization and minimal enzymatic pool in oral cavity and the potential to avoid first-pass metabolism makes the drug delivery to oral cavity by ODT attractive.14 The main challenge in the development of an ODT of DPH is effectively masking the unpleasant bitter taste.

Sophisticated taste-masking strategies, e.g.,

complexation with cation exchange resins or ion-pairing,15, 16 may reduce the bitter taste but fail to render the taste pleasant. The strategy employed in the currently marketed ODT products of DPH is to physically add sweeteners and flavors with the formulation components. However, physical separation between the drug and sweeteners during pharmaceutical processing can lead to exposure of taste buds to a high concentration of DPH before interacting with the sweetener. Thus, taste masking by simply mixing sweeteners with other formulation constituents is not very effective. Consequently, a large amount of flavor and sweetener is usually required, which results in large tablet size (e.g., 585 mg tablet weight for 12.5 mg of DPH in Benadryl children's allergy Fastmelt) and long disintegration time. Effective drug delivery by ODTs demands rapid disintegration, preferably less than 30s. Previously, we showed that salt formation with an artificial sweetener, acesulfame (Acs, pKa = 2.0, Figure 1b), was effective in masking the bitterness of berberine, a bitter drug.17 The effective taste masking by sweet salts is achieved by the concomitant release of the drug and sweetener. We hypothesized that forming an Acs salt of DPH would also effectively mask the bitter taste of DPH. 4 ACS Paragon Plus Environment

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The objective of this study was to examine the feasibility of forming a DPH salt with Acs and, if successful, to develop an ODT product with improved performance. We treated this as a test case for solving drug delivery problems using an integrated crystal and particle engineering approach.18,

19

Here, we sought the development of the most economic direct compression

process for tablet manufacturing.

Figure 1. Molecular structures of a) diphenhydramine (MW = 255.4 g/mol) and b) acesulfame (MW = 163.2 g/mol)

Materials and methods Material Diphenhydramine hydrochloride (DPH-HCl, Baikang Pharmaceutical Co., Ltd, Liaoyuan, Jilin, P.R. China), acesulfame potassium (Acs-K, Tokyo Chemical Industry Co., Ltd, Japan), mannitol (Pearlitol200SD, Roquette, France), fumed silica (CAB-O-Sil, M5-P, Cabot Corporation, Boston, MA), magnesium stearate (MgSt, Mallinckrodt Inc., St. Louis, MO), croscarmellose sodium (CCM-Na, SD-711, FMC Biopolymer, Philadelphia, PA) were used as received. DPHHCl orally disintegrating tablets (12.5mg, Benadryl children's allergy Fastmelt) and allergy relief DPH-HCl tablets were purchased from CVS Pharmacy (One CVS Drive, Woonsocket, RI). Simulated salivary fluid was prepared according to the FDA’s guidance.20 In brief, 600 mg of sodium chloride, 600 mg of urea, 750 mg of potassium chloride, 680 mg of potassium 5 ACS Paragon Plus Environment


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phosphate monobasic, 1350 mg of sodium phosphate dibasic heptahydrate, 100 mg of magnesium chloride, and 220 mg of calcium chloride dihydrate were completely dissolved in sequence in 1000 mL of deionized water with sonication at room temperature. Freshly prepared simulated salivary fluid was used for disintegration tests because, on standing, the solution became milky in about 1 – 2 hr due to precipitation of calcium phosphate. Synthesis of acesulfame salt Initially, small batches of DPH-Acs salt were prepared by mixing 5 mL of 0.1mM clear aqueous solutions of DPH-HCl and Acs-K in a 20 mL glass vial. Upon mixing, precipitation occurred immediately. To prepare bulk salt powder, a mixture of 29.18g of DPH-HCl and 20.2g of Acs-K was suspended in 200 mL of deionized water in a covered glass beaker and stirred with a magnetic stirring bar under ambient conditions for 24 h. The bulk powder was harvested by vacuum filtration and dried overnight at 50°C in an oven. Single Crystal X-Ray Diffractometry A small amount (100 mg) of the bulk DPH-Acs salt powder was dissolved in 15 mL of water under heating in a 20 mL glass vial to form a clear solution. The vial was left in a fume hood undisturbed to allow slow evaporation of water. Crystals suitable for single crystal X-ray diffraction (SCXD) experiment were obtained within one week. SCXD experiment was carried out on a Bruker-AXS Venture Photon-II diffractometer (Bruker AXS Inc., Madison, Wisconsin) equipped with a Photon-II (CMOS) detector. The data collection was performed at 123 K using a compact IµS Cu-microfocus source. Data analyses were performed using a suite of software from Bruker, including APEX3, SADABS, and SAINT. The crystal structure was solved and refined using Bruker SHELXLe. A direct6 ACS Paragon Plus Environment

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methods solution was calculated to locate most non-hydrogen atoms from the E-map. Fullmatrix least-squares/difference Fourier cycles were performed to locate the remaining nonhydrogen atoms.

All non-hydrogen atoms were refined with anisotropic displacement

parameters. All hydrogen atoms were located from the residual peaks in the Fourier map and allowed to ride on their parent atoms in the refinement cycles. Powder X-Ray Diffractometry (PXRD) Powders were characterized on a powder X-ray diffractometer (D8 Advance; Bruker AXS, Madison, WI) with Cu Kα radiation (1.54059Å). Samples were scanned between 5 to 30° 2θ with a step size of 0.02° and a dwell time of1 s/ step. The tube voltage and amperage were set at 40 kV and 40 mA, respectively. Fourier transformation infrared spectroscopy (FT-IR) FT-IR spectra of the powder samples were collected using a FTIR spectrometer (Nicolet iSTM50, Thermo Scientific) with a built-in diamond attenuated total reflection (ATR). The detector on the spectrometer was DLaTGS. For each sample, 32 scans were averaged. IR data in the range of 4000-450 cm-1 at a resolution of 2 cm-1 were processed using the software OMNIC 9.2. Raman spectroscopy Approximately 1-3 mg of powder was spread on a glass slide evenly and then flattened using a flat spatula to facilitate focusing the laser. A point of interest in the powder was focused using a 100x magnification lens of a confocal Raman microscope (Alpha300 R, WITec, Ulm,



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Germany). The spectra were then acquired using a 532 nm laser source and an integration time of 10 s. The average spectrum of two accumulations was obtained for each sample. Thermal analyses Powder samples (3∼5 mg) were loaded into Tzero hermetically sealed aluminum pans and heated from 30 to 130 °C with a heating rate of 10 °C/min on a differential scanning calorimeter (Q2000, TA Instruments, New Castle, DE) under a continuous nitrogen purge at a flow rate of 50 mL/min. The instrument was equipped with a refrigerated cooling system. The temperature and enthalpy were calibrated using high purity indium. To measure volatile content in a solid, samples (∼3 mg) were placed in an open aluminum pan and analyzed by a thermogravimetry analyzer (Q50, TA Instruments, New Castle, DE). The samples were heated from room temperature to 300 °C at 10 °C/min under 50 mL/min nitrogen purge. Hot-Stage Microscopy (HSM) Crystals were observed under a polarized light microscope (Eclipse e200; Nikon, Tokyo, Japan) equipped with a DS-Fi1 microscope digital camera for capturing digital images. Samples were heated to 130 oC, with a heating rate of 5°C/min, on a hot stage with a temperature controller (Linksys 32; V.2.2.0, Linkam Scientific Instruments, Ltd., Waterfield, UK). Solubility The aqueous solubility of DPH-Acs was determined by suspending an excess amount of solid (200 mg) in 5 mL of water under stirring at 25 °C for 72 h. The suspensions were filtered through PTEE 0.45 µm membrane filters. The filtrates were diluted with water to an appropriate concentration for measurement by a UV/Vis spectrometer (DU 530 UV/vis spectrophotometer;


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Beckman Coulter, Chaska, MN). Solution concentrations were determined using the absorbance and from a pre-constructed calibration curve. All measurements were performed in triplicate. Contact angle measurement Powders were compressed at 350 MPa pressure to prepare tablets for contact angle measurements.21 Tablets were relaxed at room temperature and 52% RH for three days prior to contact angle measurement. The contact angle of each sample was measured using the sessile drop method as a function of time on a goniometer (MAC-3, Kyowa Interface Science Co. Ltd, Japan). A drop of distilled water (~30 µL) was gently placed on the surface of the tablet using a fine needle attached to a dispenser. The shape of the water drop was recorded every 67 ms for 2 s using a high speed camera. The angle between the sample surface and the tangent line at the edge of the drop was determined using image analysis software, FAMAS3.72 (Kyowa Interface Science Co. Ltd, Japan). Three contact angle measurements were made at different locations on each tablet, and the mean and standard deviations were calculated. Dynamic Water Vapor Sorption Isotherm (DVS) Water sorption isotherms of the materials were obtained using an automated vapor sorption analyzer (Intrinsic DVS, Surface Measurement Systems Ltd., Allentown, PA) at 25 °C. The nitrogen flow rate was 50 mL/min. Each sample was first dried with dry nitrogen purge until a constant weight was obtained. Then, the sample was exposed to a series of relative humanity (RH) from 0 % to 95 %with the step size of 5 % RH. At each specific RH, the equilibration criterion of either dm/dt ≤ 0.003% or maximum equilibration time of 6h was applied. The RH was changed to the next target value once one of the criteria was met. Formulation and tablet compression 9 ACS Paragon Plus Environment


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The target loading of DPH-Acs in tablet was 40 mg, corresponding to 25 mg of DPHHCl.

This is twice the amount of DPH in a leading commercial ODT product, Benadryl

Fastmelt. Compositions of trial formulations are summarized in Table 1. DPH-Acs, after passing through a 250 µm sieve, was bottle mixed manually with other excipients for 15 min. The mixture was then mixed with magnesium stearate in a V-shaped blender (Blendmaster, Patterson-Kelly, East Stroudsburg, PA, 1 quart) for 5 min at 25 rpm before tableting. Since formulation A exhibited powder flowability unfit for high speed tableting,22 1% fumed silica was added as a flow aid to prepare formulation B. However, the powder flowability of formulation B, although improved, was still unacceptably poor. Therefore, formulation B was passed through a comil (Model U3; Quadro Engineering Corporation, Waterloo, Ontario, Canada) five times to coat nano sized fumed silica particles onto the surface of component particles. A stainless screen (round hole, 0.039’ diameter, part number 7B018R01530) was fitted on the comil and the impeller speed was 2200 rpm. To investigate the effect of mannitol on the taste score, a placebo formulation consisting of 12.5% DPH-HCl, 80.5% mannitol, 5% CMC-Na, 1% fumed silica and 1% MgSt was compressed at 5 KN to prepare tablets for assessment by the taste panel. Powders were compressed into tablets on a universal material testing machine (model 1485; Zwick/Roell, Ulm, Germany) at a speed of 5 mm/s. Compaction pressure ranged from 50 to 350 MPa, using a die (round, 8 mm diameter) and flat-faced punches. Punch tips and die wall were evenly coated with a suspension of magnesium stearate in ethanol (5%, w/v) using a brush and fan-dried before each compaction run.


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Table 1. Formulation composition of DPH-Acs ODT tablet Ingredients

% in the formulation A

B

C

DPH-Acs

20

20

20

CCM-Na

5

5

5

Mannitol

74

73

73

Fumed silica

0

1

1

Magnesium stearate

1

1

1

Total (%)

100

100

100

Compaction of formulated powders was also performed on a compaction simulator (Presster, Metropolitan Computing Company, East Hanover, NJ) to simulate a 10-station Korsch XL100 tablet press. The dwell time was set at 20 ms, corresponding to a production speed of 61,600 tablets/h.

Key physical parameters during tableting, include compaction force,

displacement of punches, and ejection force were collected.23 In a preliminary study of the formulations, a round flat-faced tooling (9.5 mm) was used to make cylindrical tablets for easy determination of tablet volume and tensile strength.

To prepare a batch of tablets for

characterizing tablet performance, round standard concave tooling (8.67 mm diameter) was used. Tablets were relaxed under ambient environment for at least 24 h before being broken diametrically using a texture analyzer (TA-XT2i; Texture Technologies Corporation, Scarsdale, NY). Tablet tensile strength was calculated from the breaking force and tablet dimensions following a standard procedure.24 Tablet porosity was calculated from tablet density and true density.

The true density of formulation was measured using a helium pycnometer

(Ultrapycnometer1000, Quantachrome Corporation, Boynton Beach, FL). 11 ACS Paragon Plus Environment


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Powder flowability Powder flowability was measured using a ring shear cell tester (RST-XS; Dietmar Schulze, Wolfenbüttel, Germany) with performance verified using a limestone powder standard. A 10mL cell was used for collecting data at the preshear normal stresses of 1, 3, 6, and 9 kPa using the same set of experimental parameters as in previous studies.22, 25 From the shear cell measurements, powder flowability index (ffc) was calculated. Expedited friability Tablet friability profile of each formulation was determined using an expedited method.26, 27

Convex tablets prepared under different compression forces were individually coded and

loaded into a friabilator (Model F2, Pharma Alliance Group Inc., Santa Clarita, CA) at 25 rpm for 4 min. Percentage weight loss of each tablet was calculated and plotted against compaction force. Customized disintegration test Tablet disintegration time as a function of compaction pressure was determined using a set up shown in Figure 2, which simulates the conditions in oral cavity as previously described.28-33 In brief, one convex tablet was placed in the middle of a small round container (diameter 18.2mm). A spherical stainless steel indenter (3.2 mm in diameter), attached to a texture analyzer, approached the center of the tablet at a speed of 0.01 mm/s until a force of 3.0 N was attained. After holding for 30 s, 2.0 mL of freshly prepared simulated salivary fluid was added using a syringe to cover the top surface of the tablet. The indenter moved downward to maintain the prescribed force of 3.0 N as the tablet began to disintegrate after being exposed to the fluid (Figure 2a).

From the disintegration profile (distance-time curve) (Figure 2b), 12 ACS Paragon Plus Environment

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disintegration time was taken as the time difference between the two plateau regions. The first plateau region corresponds to the stable contact between the probe and the dry tablet. The second plateau region corresponds to the stable contact between the probe and bottom of the container after complete disintegration of the tablet.

(a)

(b)

Figure 2. Disintegration testing: a) schematic representation of the apparatus, b) disintegration profile.

In vivo test of tablets A total of 14 healthy volunteers (10 males and 4 females) were randomly divided into two groups in a crossover study to test in vivo disintegration time, bitterness, and grittiness of the commercial DPH-HCl ODT and DPH-Acs convex tablets (this work). The volunteers refrained from eating and drinking for at least 1 h before the study. Tablet was put onto the tongue and the mouth was closed.

The individual volunteers reported disintegration time, bitterness and

grittiness immediately after the tablet disintegration and after 5 mins following a scoring system shown in Table 2. Before testing the second tablet, the remaining material from the first test was removed from the oral cavity and the volunteers gargled with purified water and waited for at least 30 min until no residual taste persisted. After the crossover study, placebo tablets were 13 ACS Paragon Plus Environment


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tested by all volunteers. Then, commercial DPH-HCl tablets (250 mg) were tested by all volunteers, where only the bitterness score was recorded for the commercial tablets. This was done at the end because of its known intense bitterness. Table 2. Scoring system for taste assessment Bitterness score description

0 Sweet

1 Slightly sweet

Grittiness Score description

0 Smooth (no particle detected)

2 No taste

1 Few particles detected

3 Slightly bitter

2 More particles detected

4 Bitter

3 Many large particles detected

5 Extremely bitter

4 Extremely gritty

Results and discussion The powder prepared by suspending DPH-HCl and Acs-K in water showed distinct PXRD pattern than those of both DPH-HCl and Acs-K (Figure 3), where new unique peaks were observed at 9.19, 18.52, 28.26◦. At the same time, characteristic peaks of DPH-HCl (10.49, 12.48, 24.96◦) and Acs-K (8.64, 17.10, 25.66◦) were absent. Therefore, DPH-HCl and Acs-K reacted to form a new solid form. Characteristic peaks of both of DPH-HCl and Acs-K in its IR and Raman spectra were observed in those of DPH-Acs (Figure 4). This suggests both DPH and Acs are in an ionic state, i.e., it is a DPH-Acs salt.


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Figure 3. Powder X-ray diffraction patterns of DPH-HCl, Acs-K, and DPH-Acs (both experimental and calculated).

(a)

(b)

Figure 4. Vibrational spectra of DPH-HCl, Acs-K, and DPH-Acs: a) FT-IR and b) Raman spectroscopy

The crystal structure is monoclinic (space group P21/n) (see Table S1 for detailed crystallographic information), where the Acs-H proton is transferred to DPH and the DPH cation and Acs anion ratio is 1:1 (Figure 5a). Thus, DPH-Acs is a mono-salt. A strong N-H···O hydrogen bond interaction (dD···A = 2.738 Å, θ = 158.57o) between DPH cation and Acs anion can 15 ACS Paragon Plus Environment


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be identified (Figure 5a).

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Detailed hydrogen bond information of this crystal structure is

summarized in Table S2. The unit cell content (Z = 4) viewed into b-axis is show in Figure 5b.

(a)

(b)

Figure 5. Crystal structure of DPH-Acs: a) asymmetric unit and b) unit cell viewed along b axis.

The PXRD pattern calculated from the crystal structure matched well with the experimental PXRD pattern (Figure 3). The slight shift to higher two theta values of some peaks in the calculated PXRD pattern is attributed to the lower temperature (123K) at which the structure was solved. Difference in relative peak intensity is attributed to the effects of preferred orientation phenomenon of the experimental PXRD. Overall, this confirms the phase purity of the bulk DPH-Acs salt powder. The DSC thermogram of DPH-Acs shows an onset melting temperature of 120.16oC (∆Hf = 114.4 J/g) (Figure 6). The flat baseline also suggests phase purity of the material. Melting range observed on HSM, 123- 125oC, was slightly higher than that by DSC. The discrepancy is likely due to thermal lag in HSM experiment (Figure 6). The melting point of DPH-Acs is lower than those of DPH-HCl (166 ℃) and Acs-K (225 ℃). Thermogravimetric data suggests that DPH-Acs underwent negligible weight loss (0.3%) up to 150 ℃ (Figure S1).


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25 ℃

123 ℃

125 ℃

Figure 6. Thermal behavior of DPH-Acs salt characterized by differential scanning calorimetry and hot stage microscopy.

Wettability of a solid, which may be evaluated by the contact angle (CA), is a property critical for understanding and controlling several important pharmaceutical phenomena, such as tablet disintegration and dissolution. To minimize possible impact of surface roughness on measured CA, a relatively high compaction pressure of 350MPa was used to produce tablets with smooth surface (tablet porosity was 0.11±0.01 and 0.13±0.01for DPH-Acs and DPH-HCl, respectively). The CA of DPH-Acs (60.03 ±0.56°) is significantly higher than that of DPH-HCl (7.50°±1.25), suggesting that DPH-Acs is significantly less wettable than DPH-HCl (Figure 7a). The moisture sorption isotherm suggests that deliquescence of DPH-HCl occurred at 85% RH (Figure 7b). In fact, the powder turned into a solution at the end of the experiment. In contrast, DPH-Acs adsorbed less than 0.2%water at 85% RH. DPH-Acs is nonhygroscopic and DPH-HCl is very hygroscopic base on the hygroscopicity classification system.34 Both the lower



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CA and higher hygroscopicity of DPH-HCl are consistent with its much higher aqueous solubility (1g/mL) compared to DPH-Acs (~10 mg/mL).

(a)

(b)

Figure 7. Comparison of DPH-Acs and DPH-HCl properties: a) wettability and b) hygroscopicity.

Tabletability of the as-received DPH-HCl was very poor with a maximum tensile strength of ~0.3 MPa at 100 MPa pressure (Figure 8). This may be one reason why drug loading is relatively low, 10% (wt %), in the commercial 25 mg DPH-HCl oral tablet and 2.1% in the 12.5 mg DPH-HCl ODT. Indeed, the poor tabletability could have been caused by the large particle size (350 - 500 µm) of as-received DPH-HCl.35,

36

To probe the effects of particle size on

tabletability, sieved fraction (< 250 µm) of milled DPH-HCl was also studied (Figure S2). However, the tabletability of smaller DPH-HCl was only slightly improved, where the maximum tensile strength was ~0.5 MPa at 200 MPa pressure (Figure 8). In contrast, tabletability of DPHAcs was much better than that of DPH-HCl, reaching ~2.2 MPa tensile strength at 200 MPa pressure (Figure 8). The much improved tabletability of the DPH-Acs salt may be attributed to


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its higher plasticity than DPH-HCl. In fact, single crystals of DPH-HCl underwent brittle fracture when bent but DPH-Acs could sustain a significant degree of plastic deformation without breaking (Figure S3). Such higher plasticity of DPH-Acs would result in larger bonding area and, therefore, stronger tablets according to the bonding area – bonding strength interplay model.13, 37 Tensile strength of DPH-Acs tablet increased with increasing pressure from 50 MPa to 200 MPa but decreased when the pressure was further increased to 300MPa, indicating the occurrence of over-compression. The decreased tensile strength was accompanied by tablet lamination during the diametrical breaking test for tablets compressed at ≥ 250 MPa, which was absent for tablets compressed at 1.0 %) for routine packaging, shipping, and handling. To deal with this problem, peelable blister packages are commonly used for ODT products, such as Benadryl children's allergy Fastmelt. However, packaging ODTs in multi-dose bottles is more economical, but the friability must be much less. This requires careful design of the formulation for optimum tableting performance as well as exploration of the design space of the key parameter, compaction force, for a given formulation to achieve a balance between the short disintegration time (30 s) and low friability (< 0.8%).

For convex shaped formulation C tablets, the

disintegration time increased linearly within creasing compaction force (R2 = 0.98, Figure 11). Tablet friability, on the other hand, decreased sharply with increasing compaction force, which 22 ACS Paragon Plus Environment

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was described by a forth order polynomial function (R2 = 0.96). At the disintegration time of 30 s, the upper bound of the 95% confidence level of compression force was 7.2 kN, while the lower bound of the 95% confidence interval of 0.8% friability was 2.9 kN. Thus, for this tooling, any compression force between 2.9 and 7.2 kN can be used to manufacture tablets with < 30 s disintegration time and < 0.8% friability. This wide range of compression force provides high flexibility in manufacturing DPH ODT with desired properties.

Furthermore, the relative

standard deviation (RSD) of tablet weight was 1.6% (199.4 ± 3.2 mg) of formulation C when compressed at a high tableting speed corresponding to a dwell time of 20 ms (61,600 tablets/h). This is better than the commercial DPH-HCl ODT (RSD = 2.4%) (Figure S4).

Thus,

formulation C is suitable for commercial production at a high speed.

Figure 11. Dependence of tablet disintegration time and friability of formulation C on compaction force.

To confirm the clinical performance of formulation C tablets, in vivo disintegration time, bitterness, and grittiness were assessed using tablets compressed at 5.0 KN. The disintegration time of the ODTs of formulation C (~51 s) was about one tenth that of the commercial DPH HCl 23 ACS Paragon Plus Environment


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ODT tablet (~500 s, Table 3). The DPH-Acs ODT also exhibited slightly less grittiness than the commercial DPH-HCl ODT. The bitterness score of the DPH-Acs ODT (2.3±1.6 immediately after tasting) was significantly lower than that of the 25 mg DPH-HCl tablet (4.9±0.4), suggesting effective masking of the bitterness. To determine whether the effective taste masking was due to use of mannitol or sweet salt, a control ODT with DPH-Acs replaced by an equivalent amount of DPH-HCl was assessed. The difference in API weight was compensated by adding more mannitol SD200. Even with slightly higher (80.5%) mannitol in the control formulation, the taste score (4.2±0.8) was similar to the commercial oral tablet, which is extremely bitter. This suggests that the use of DPH-Acs was key in masking the taste. The DPH-Acs based ODT in this work has a higher bitterness score (~2.3) than that of Fastmelt® ODT (~0.1). This is attributed to the lower drug loading and a large amount of grape flavor used in the Fastmelt® ODT. As such, a lower bitterness score is expected with the use of grape flavor and/or a lower drug loading.

However, it was deemed unnecessary since the bitterness was considered

acceptable by the taste panel and incorporation of a large amount of grape flavor is expected to prolong the disintegration time.

Although forming a salt with an artificial sweetener was

effective in masking bitter taste of DPH, the broad applicability of this approach remains to be tested unless a mechanism that supports the universality of such an approach is proven.


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Table 3. In vivo performance compared between our product and commercial product. Disintegration time

Bitterness score

Grittiness score

(s)

Immediately

5 mins

Immediately

Formulation C

51 ± 26

2.3 ± 1.6

2.3 ± 1.3

1.1 ± 1.2

control formulation

67±12

4.2±0.8

3.3±1.3

1.4±0.5

Commercial ODT(Fastmelt)

500 ± 255

0.1 ± 0.4

0.9 ± 0.8

1.5 ± 1.4

Commercial oral tablet

NA

4.9±0.4

4.9±0.4

NA

Stability of the DPH-Acs based ODT product was conducted in an open dish under 25 ℃/57 % RH, 40 ℃/11 % RH and 40 ℃/75 % RH conditions for one month. The disintegration time after the stability study was 15±4, 16±2 and 53±9 s, respectively.

Although the

disintegration time was significant prolonged from 12± 2 s to 53±9 s (n=8) at 40 ℃/75 % RH, the tablet weight only slightly increased by 0.20 % and the friability increased from 0.40 % to 0.91 %. The tablet breaking force was essentially unchanged (35.2±1.8 N and 35.3±1.8 N) by storage at 40 ℃/75 % RH. Although a clear explanation is elusive, this is similar to a recent observation that stability storage under the accelerated conditions retarded disintegration but did not change breaking force.47 The data do suggest that the DPH-Acs based ODT should be protected from high temperature and humidity to maintain the physical stability. To summarize, the development of a new ODT product of DPH with improved pharmaceutical properties only required ~15 g of DPH and 2 months of time, including one month stability study.

This high development efficiency was attributed to the seamless

applications of 1) crystal engineering to fundamentally improve the hygroscopicity, taste profile, and tabletability of DPH; 2) particle engineering, i.e., nano-coating, to effectively improve



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powder flowability; 3) selection of excipients based on their functionality and materials properties; and 4) identification of process design space guided by predictive techniques (Figure 12). This strategy is expected to be effective in developing high quality drug products of other challenging drugs. The success exemplified by the DPH ODT case demonstrates the power of the materials science based approach in realizing quality-by-design principle in pharmaceutical development.

Excipient selection Tablet size

Grittiness

Crystal engineering

Hygroscopicity

Tabletability

Taste masking

ODT

Disintegration

Flowability Friability

Particle engineering

Process control

Figure 12. Materials science based strategies used in this DPH-Acs ODT product development.

Conclusions Forming a sweet salt with Acs significantly improved several important pharmaceutical properties of DPH, including hygroscopicity, compaction properties, and taste. On the basis of such a pharmaceutically enhanced solid form of DPH, expedited development of a high quality ODT product using a minimum amount of drug was attained through careful excipient selection and process optimization. The new DPH ODT product exhibited low weight variation, short 26 ACS Paragon Plus Environment

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disintegration time, improved palatability, reduced grittiness, and good stability.

The

development approach that engages the integrated crystal and particle engineering plays a powerful role in realizing the quality-by-design objective of pharmaceutical drug development. Supporting Information. Single crystal X-ray data collection and refinement of DPH-Acs, hydrogen bonding and thermogravimetric data of DPH-Acs, microscopic images, moisture sorption isotherm of mannitol, flowability of mannitol and Avicel PH102, tablet weight variations

Acknowledgements We are grateful for resources from the University of Minnesota through the Minnesota Supercomputing Institute. Some of the experiments were performed at the University of Minnesota I.T. Characterization Facility, which receives partial support from the NSF through the NNIN program. We thank Kunling Wang for her help in collecting Raman spectroscopic data and members of the taste panel for their contributions. C.W. thanks Ms. Lily Liu for her useful comments during the preparation of this manuscript.

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Table of Contents Graphic Title: Expedited development of diphenhydramine orally disintegrating tablet through integrated crystal and particle engineering Authors: Chenguang Wang, Shenye Hu, and Changquan Calvin Sun

Excipient selection

Hygroscopicity

Tablet size

Grittiness

Tabeletability

ODT

Taste masking

Disintegration

Flowability

Particle engineering

Crystal engineering

Friability

Process control

Synopsis: The formation of a sweet salt with acesulfame significantly improved taste and mechanical properties of diphenhydramine, which enabled the successful development of an orally disintegrating tablet product through direct compression.

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Expedited Development of Diphenhydramine Orally Disintegrating

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