A platform direct compression formulation for low dose sustained-release tablets enabled by a dual particle engineering approach

Accepted Manuscript A platform direct compression formulation for low dose sustained-release tablets enabled by a dual particle engineering approach

Wei-Jhe Sun, Hongbo Chen, Aktham Aburub, Changquan Calvin Sun PII: DOI: Reference:

S0032-5910(18)30898-2 doi:10.1016/j.powtec.2018.10.054 PTEC 13829

To appear in:

Powder Technology

Received date: Revised date: Accepted date:

6 February 2018 23 October 2018 26 October 2018

Please cite this article as: Wei-Jhe Sun, Hongbo Chen, Aktham Aburub, Changquan Calvin Sun , A platform direct compression formulation for low dose sustained-release tablets enabled by a dual particle engineering approach. Ptec (2018), doi:10.1016/ j.powtec.2018.10.054

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ACCEPTED MANUSCRIPT

A platform direct compression formulation for low dose sustained-release tablets enabled by a dual particle engineering approach

Pharmaceutical Materials Science and Engineering Laboratory, Department of Pharmaceutics,

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Wei-Jhe Suna, Hongbo Chena, Aktham Aburubb, Changquan Calvin Suna,* [email protected]

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College of Pharmacy, University of Minnesota, 9-127B Weaver-Densford Hall, 308 Harvard Street S.E., Minneapolis, MN 55455 b Small Molecule Design and Development, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285

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Corresponding author at: 9-127B Weaver-Densford Hall, 308 Harvard Street S.E.Minneapolis, MN 55455.

ACCEPTED MANUSCRIPT Abstract Content uniformity (CU) is a well-recognized challenge for low-dose direct compression (DC) tablet formulations.

Using a dual particle engineering approach that involves a) forming a

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segregation-resistant drug-carrier composite to improve CU and b) nanocoating HPMC to enhance

sustained-release (SR) tablets with excellent CU.

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flowability, we have developed a platform DC formulation for preparing low-dose drug In addition to demonstrated robustness in

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manufacturability, this platform formulation has the flexibility for modifying drug release rate.

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Thus, it is useful for expedited and material-sparing development of low dose SR tablets using the

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economical DC process.

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Keywords: Sustained release, particle engineering, direct compression, nanocoating,

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acetaminophen, celecoxib, nicotinamide, tableting

Introduction

Many low dose drugs are delivered in the form of oral tablets.

Well-known examples include

hormones for replacement therapies and cytotoxic compounds for cancer therapy.

Modern drug

discovery has led to more active pharmaceutical ingredients (API) with high specificity and thereby high potency.[1]

Thus, the demand for the formulation and manufacturing of low dose drug

products has steadily increased.

The development of tablets of potent drugs poses a number of

ACCEPTED MANUSCRIPT challenges, such as a) poor content uniformity (CU), b) high manufacturing cost due to stringent safety precautions to prevent worker exposure, and c) the need for a sophisticated analytical procedure to quantify drugs.[2-5]

Among these, CU is of the greatest concerns because sub-potent

tablets are ineffective, while super-potent tablets can result in serious side effects.

Hence, inadequate

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product Critical Quality Attribute (CQA) directly linked to the patient.

CU is a drug

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uniformity is not acceptable as it could result in failure of therapy. Therefore, unsatisfactory tablet

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CU leads to batch rejection.

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Normally, the smaller fluctuation in plasma drug concentration elicited by the sustained drug release minimizes the risk of side effects of drugs, because they can provide relatively more

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consistent drug plasma concentration over a longer period for optimum therapeutic outcomes.[6-9] The clinical outcomes are usually better with improved patient compliance; a consequence of less However, problems arise when the CU of sustained-release (SR) tablets is

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frequent dosing.[10]

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poor due to higher probability of an incorrect dose over a long period of time with a SR tablet as

administered.

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compared to an immediate release (IR) tablet, which arises from the less frequent doses If the drug content in each tablet is highly variable, the chance of plasma drug

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concentration deviating from the optimum concentration is greater for SR tablets, which is specially

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of concern to drugs exhibiting a narrow therapeutical window. Hydroxypropyl methylcellulose (HPMC) is the most commonly used material for preparing matrix SR tablets, since it is nontoxic, easy to handle, and available in several viscosity grades.[11, 12]

Drugs are released by diffusion through the hydrated HPMC gel layer, with erosion as an

alternative mechanism.[13-15]

However, HPMC has poor flow properties and is, therefore, unfit

for the preferred most cost-effective direct compression (DC) process for manufacturing tablets. When the dose is extremely low, the poor flowability of HPMC exacerbates the difficulty in

ACCEPTED MANUSCRIPT achieving good CU of tablets by DC. As such, the development of low dose SR tablets using HPMC based formulations, which has been primarily handled empirically and on a case by case basis, is often problematic.

The purpose of this work was to develop a platform DC formulation

for developing HPMC based matrix SR tablets of low dose drugs with both excellent CU and robust

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manufacturability. We previously developed a platform DC formulation for IR low dose tablets using a

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drug-porous carrier approach. We anticipated the same particle engineering approach is equally

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effective for preparing SR tablets. The additional challenge was to assure manufacturability of the formulation by improving flowability of HPMC, which could be achieved by using the nanocoating

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strategy.[16, 17]

Materials and methods

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Materials

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Three drugs with very different aqueous solubilities were used in this work: nicotinamide (NIC; 1000 mg/mL; Sigma-Aldrich, St. Louis, MO), acetaminophen (APAP; 12.8 mg/mL; Frank W.

Although not potent drugs themselves, these model drugs are appropriate to test the

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India).

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Horner Ltd., Municipality, Canada), and celecoxib (CEL; 0.0056 mg/mL; Aarti Drugs Ltd., Mumbai,

robustness and performance of the proposed platform formulation.

Following the success in the

earlier development of an IR tablet platform, magnesium aluminometasilicate

(Neusilin S1, Fuji

Chemical Inc., Toyama, Japan), with specific surface area of 110 m2/g and water adsorbing capacity of 1.0 mL/g) [18] was chosen as a porous carrier.

Hydroxypropyl methylcellulose (HPMC K4M,

Ashland Inc., Covington, KY), microcrystalline cellulose (Avicel PH102, FMC, Philadelphia, PA), lactose monohydrate (Fast-Flo, Foremost Farms, Dallas, TX), Colloidal silica (M-5P, Cab-O-Sil;

ACCEPTED MANUSCRIPT Cabot Corporation, Boston, MA), and magnesium stearate (Covidien, Dublin, Ireland) were also used for formulating tablets.

Polysorbate 80 (Tween 80, VWR, Radnor, PA) was used as a

surfactant to prepare dissolution media when needed.

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Methods

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Preparation of drug–carrier composite

Under stirring, the solution was added to the Neusilin powder in 1:1 (v/w)

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desired concentration.

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A model drug was dissolved in dimethylformamide (DMF) to prepare a solution with the

ratio and was absorbed completely and immediately into Neusilin without forming a paste. This

requiring filtration before drying.

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solution volume was chosen because it nearly saturated Neusilin to ensure uniformity without Since the volume of the added solution is fixed, the amount of

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drug loaded into the carrier only depended on the drug concentration in solution (Table 1).

Three

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levels of drug contents (5.0%, 0.5%, and 0.05%) were prepared for CEL-carrier composite but only two levels (5.0% and 0.5%) of drug contents were prepared for NIC-carrier and APAP-carrier

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composites. DMF was removed by drying at 55 °C for 24 h.[19]

To minimize any effect of

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uncontrolled water content variations in drug-carrier composite, the dried drug–carrier composite was stored in a 43% relative humidity (RH) chamber, which was close to the environment RH, until The room temperature was 23 ± 2 °C.

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further use.

Dry Powder Coating of HPMC Particles with Silica Nanoparticles HPMC was surface-coated with 1.67% (w/w) silica nanoparticles by milling in a conical mill. Approximately equal volumes of HPMC and silica nanoparticles were mixed and passed through a sieve with 355 μm opening size. geometric dilution.

The sieved powder was then mixed with the remaining HPMC by

The final blend was then passed through a conical mill (Model U3; Quadro

ACCEPTED MANUSCRIPT Engineering Corporation, Waterloo, Ontario, Canada), fitted with a stainless screen (round hole, 0.039’ diameter, part number 7B018R01530) and a square bar impeller.

The lowest impeller speed

(2200 rpm) was used to minimize mechanical stress on the powder.[20]

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Preparation of DC tablet formulation Blends were prepared by

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The composition of the SR tablet formulation is shown in Table 2.

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mixing the drug-carrier composite with nanocoated HPMC, microcrystalline cellulose, and lactose

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monohydrate in a V-shaped laboratory blender (Blend Master; Patterson–Kelley, East Stroudsburg, PA) at 25 rpm for 10 min. Magnesium stearate was then added and mixed for an additional 5 A formulated powder without any drug was also prepared as a control

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minutes at 25 rpm.

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temperature before tablets production.

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formulation. After preparation, the formulation powder was stored in 43% RH chamber at room

Differential scanning calorimetry (DSC)

Briefly, an approximately 2-4 mg of sample was accurately weighed and sealed

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New Castle, DE).

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Thermal behavior was analyzed by a differential scanning calorimeter (TA Instruments Q2000,

in an aluminum pan. Each sample was heated, under 25 mL/min nitrogen purge, from 25 °C to 10

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°C above the melting point of the corresponding crystalline drug at a heating rate of 10 °C/min.

To

ensure detection of signals by the DSC, a composition containing 10% drug in the carrier was studied.

Powder X-ray diffraction analysis (PXRD) Solid state structure of the sample was characterized by powder X-ray diffraction analysis (PANalytical X'pert pro, Westborough, MA) using Cu-Kα radiation source (40 kV and 40mA) at

ACCEPTED MANUSCRIPT room temperature.

A diffraction pattern was obtained by scanning the sample from 3° and 35°

with a step size of 0.017°.

Only composites containing 10% of drugs were studied to ensure

adequate signal intensity of diffraction patterns.

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Scanning Electron Microscopy (SEM)

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The surface morphology of drug-Neusilin composite was observed using scanning electron

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microscopy (JEOL 6500F; JEOL Ltd., Tokyo, Japan) under a vacuum of 10−4–10−5 Pa. Samples were coated with a thin layer of platinum (thickness ∼50 Å) using an ion-beam sputter

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(IBS/TM200S; VCR Group Inc., San Clemente, CA) before SEM analysis.

Content uniformity

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Individual tablets were ground by a mortar and pestle and then suspended in methanol and

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rigorously stirred for 30 minutes. The suspension was filtered through a hydrophobic PTFE 0.45 μm membrane, and the UV absorbance of the filtered solution was measured using a UV/Vis

The drug concentration was determined from the UV absorbance based on

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background correction.

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spectrophotometer (DU Series 500, Beckman Instruments, Fullerton, CA) with appropriate

a calibration curve previously constructed for each drug. The wavelengths were 262 nm for

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nicotinamide, 247 nm for acetaminophen, and 252 nm for celecoxib.

Powder flowability

The flow property of the powder was measured in triplicate using a ring shear tester (RST-XS, Dietmar Schulze, Wolfenbüttel, Germany).[21]

A shear cell (30 mL volume) was used for testing

powder flowability at preshear normal stresses of 1, 3, 6, and 9 kPa.

Sample preparation and

instrument operation conformed to the USP method on shear cell testing.[22]

Under each preshear

ACCEPTED MANUSCRIPT normal stress, shear tests were subsequently performed at a total of five progressively increasing normal stresses between 230 Pa and the corresponding preshear normal stress to construct a yield locus. Unconfined yield strength (fc) and major principal stress (σn) were obtained from each yield locus by drawing Mohr’s circles. The flowability index, ffc, was calculated using equation (1):[23] 𝜎𝑛

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(1)

𝑓𝑐

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𝑓𝑓𝑐 =

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Avicel PH102, a reference powder for adequate flowability, was also tested under the same

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conditions.[24]

Powder tabletability

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Powders were compressed into tablets (200 mg weight) using a universal materials testing

punches.

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machine (Zwick-Roell MaterialPrufung 1485, Ulm, Germany) with 8.0 mm round, flat-faced After preparation, tablets were relaxed for 24 h in a 43% RH chamber at ambient

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temperature before further characterization.

The tablet diameter (d) and thickness (h) were

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measured by a digital caliper, and tablet breaking force was determined using a texture analyzer (TA-XT2i, Texture Technologies Corp., Scarsdale, NY) at a speed of 0.01 mm/s with a 5 g trigger

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force. The tablet tensile strength (σ) was calculated from the breaking force (F) using equation

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(2):[25]

σ=

2𝐹 𝜋𝑑ℎ

(2)

Tablet friability Tablet friability of each formulation was determined using an expedited method.[26]

For

each powder, 15-20 tablets prepared at different compaction pressures were coded and weighed before being loaded into a friabilator (Model F2, Pharma Alliance Group Inc., Santa Clarita, CA) at

ACCEPTED MANUSCRIPT 25 rpm for 4 minutes.

The percentage weight loss was calculated for each tablet and plotted

against compaction pressure.

The threshold tensile strength corresponding to 0.8% friability was

determined from the friability plots. Dissolution study of tablets

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Drug dissolution was performed using the USP II apparatus (Varian VK 705DS, Varian Inc.,

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Palo Alto, CA) in 500 mL, pH 6.8 phosphate buffer for both NIC and APAP tablets.

When CEL

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tablets were tested, 0.5% Tween 80 was used to facilitate the dissolution of poorly soluble CEL.[27]

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The temperature was maintained at 37 ± 0.5 ℃, and the paddle speed was 50 rpm.

A SR tablet

prepared under 150 MPa was put into a sinker to prevent sticking on the vessel bottom.

Aliquots

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of the medium (3 mL) were taken and immediately replaced with fresh medium at predetermined time points. Aliquots were filtered through a 0.45 μm membrane, and the concentration was

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determined using spectrophotometry as described above.

Results and Discussion

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Flowability Enhancement by Surface Silica Deposition on HPMC

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Similar to the previous observations that particle coating with colloid silica significantly improved flowability of excipients as well as formulations,[16, 17, 28, 29] the flowability of HPMC

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was also significantly improved after coating with silica (Figure 1a).

Deposition of silica nano

particles on HPMC particles after coating is confirmed by SEM (Figure 1b).

Three milling cycles were sufficient to render HPMC flowability better than that of Avicel PH102, indicating suitability for high speed tableting. [24]

The powder flowability continued to

improve with repeated milling up to 20 cycles but deteriorated with further milling.

The initial

increase in flowability by milling may be attributed to the breakage of silica aggregates and better

ACCEPTED MANUSCRIPT surface coverage of HPMC particles by the silica particles.

The surface coverage by silica

nanoparticles after 20 cycles was optimum, where breakage of large silica agglomerates was complete. Further milling caused particles to be removed from HPMC surfaces due to entrapment within the groove and crevices.[16]

Based on this result, a batch of HPMC prepared with 20

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milling cycles was prepared and used in subsequent studies.

Figure 2 shows Neusilin S1 and drug-Neusilin composites.

No significant changes in particle

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Characterization of API–Neusilin composites

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shape were observed before and after loading 5% of all three model drugs (Figure 2a).

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was no sign of drug on the surface of carrier at high magnification (Figure 2b). Thus, drug

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primarily remained within the carrier particles.

APAP, and CEL, respectively.

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When heated, endothermic melting peaks were observed at 130°C, 170°C, and 163°C for NIC, However, neither Neusilin nor drug-Neusilin composites exhibit

This was further supported by the observation that no diffraction peaks were observed

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crystalline.

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any obvious thermal events up to 180°C (Figure 3a). Thus, drugs in the composites were not

in all drug-Neusilin composites (Figure 3b). The diffused halos in the composites resembled that

DSC data.

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of Neusilin, confirming the absence of crystalline drug in the composite, which is in agreement with

Flowability of Neusilin was not significantly different from NIC-Neusilin (p > 0.05) but was significantly lower than the APAP-Neusilin and CEL-Neusilin composites (p < 0.05) (Figure 4a). However, the superior flowability of all drug-Neusilin composites than Avicel PH102 suggests suitability of high speed tableting.

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Consistent with the previous observations,[19] drug loading did not significantly change tablet tensile strength when compared to Neusilin (Figure 4b). on tableting performance of Neusilin.

Here, the 5% drug had a negligible effect

Importantly, tablet strength was excellent, since they were

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above 2MPa tensile strength, which is thought to be adequate mechanical strength for tablets.[30]

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Content Uniformity of Formulated Tablets

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For the tablets prepared from a physical mixture of CEL and Neusilin, only at 1.0% drug

CEL loading was 0.1% and 0.01% (Figure 5a).

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loading was mean content close to 100% of the target, but deviations were seen from 100% when In addition, the relative standard deviation (RSD) This clearly highlights

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increased from 3.6% at 1% drug loading to 34.1% at 0.01% drug loading. the CU risk associated with low drug load tablets.

In contrast, excellent dose accuracy was

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obtained (98.3 – 100.5% of the target value) for drug-Neusilin composite based tablets regardless of

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drug loading. Moreover, the RSD was less than 1.0% for all three drug loadings (Figure 5a). Thus, superior CU was attained even for extremely low dose drug, when CEL-Neusilin composite This was also consistent with excellent CU observed in an IR tablet

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was used in the formulation.

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matrix.[19]

Similar to the results in CEL, excellent dose accuracy and precision was also demonstrated for

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NIC and APAP at 0.1% drug loading (Figure 5b), where the average drug content was close to 100% and the RSD was less than 1.0% in all cases. Thus, neither the chemical structure nor the aqueous solubility had an effect on the uniform distribution of drugs.

Flowability, Tabletability, and Tablet Friability of the platform SR formulation All formulations had much higher flowability than Avicel PH102 (Figure 6a), indicating they are all suitable for high speed tableting.

This is not surprising, since the main components in

ACCEPTED MANUSCRIPT the formulation, lactose, nanocoated HPMC, drug-Neusilin composite, all exhibited better flowability than Avicel PH102.

Tablet tensile strength of all three drug-carrier composite based formulations (1% drug loading The tabletability profiles

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in tablet) increased with increasing compaction pressure (Figure 6b).

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only varied slightly among the three different formulations and placebo formulation. The friability

This is excellent, because sufficiently strong tablets could be made

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50 MPa compaction pressure.

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plots (Figure 6c) showed that the tablet weight loss was less than 0.8%, for tablets compressed at >

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under a relatively low compaction pressure.

The insensitivity of powder flowability and tabletability to the type of loaded drug in the

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drug-Neusilin composite based formulations suggested robust manufacturability of these

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In-Vitro Release of Tablets

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formulations, which is required for any successful platform SR tablet formulation.

Dissolution experiments were carried out in pH 6.8 phosphate buffer solutions for both NIC For CEL tablets, 0.5% (w/v) Tween 80 (CMC = 0.0012%, w/v) was added to

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and APAP tablets.

dissolution medium to maintain the sink condition through micellar solubilization of CEL. Although all formulations contained 1.0% (w/w) drug, equivalent to 2.0 mg of drug per tablet, the dissolution profiles were very different (Figure 7a).

The rate of drug release follows the order of

the solubility, i.e., NIC > APAP > CEL.

Conceivably, dissolution rate could be controlled by incorporating different amounts of HPMC

ACCEPTED MANUSCRIPT in the formulation. For APAP-Neusilin composite, dissolution rate was indeed slower using a higher amount of HPMC in the final tablet formulation (e.g., 0%, 15%, 30%, and 60%, w/w) (Figure 7b). This is because the higher ratio of HPMC can retard the penetration of water into tablet and, therefore, the rate of tablet hydration.

The more viscous HPMC gel layer also Drug release rates can be

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decreased drug diffusion and resisted the erosion more effectively.

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characterized by the area under the curve (AUC), mean dissolution time (MDT), and dissolution

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half time (t50%), where a higher MDT, longer t50%, or a lower AUC means slower drug release. Here,

(Table 3).

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drug release rate is progressively reduce with increasing amount of HPMC by all three measures The results suggest that dissolution rate can be modulated as needed using this platform For the SR formulation

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formulation by adjusting the amount of HPMC in the formulation.

platform to be successful, formulations containing different amounts of HPMC must also exhibit Nanocoated HPMC exhibited both good flowability and

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acceptable manufacturability.

release rates.

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tabletability regardless of the HPMC content (Figure 8), which was varied to achieve different drug In fact, flowability and tabletability data of formulations containing 0% - 100%

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nanocoated HPMC are both excellent (Figure 8).

Thus, a dual particle engineering strategy,

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involving the use of drug-carrier composite and nanocoated HPMC, enabled a platform capable of

Conclusion

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developing manufacturable SR tablet formulations for low dose APIs using the DC process.

The dual particle engineering approach, i.e., forming a segregation-resistant drug-carrier composite to improve content uniformity and nanocoated HPMC to enhance flowability, was successfully used to enable the development of a platform formulation for manufacturing low dose SR tablets with superior content uniformity using DC process.

While having the ability to modify

drug release rate, this platform formulation also exhibits excellent manufacturability.

Thus, it is

ACCEPTED MANUSCRIPT useful for expedited development of low dose SR tablets using the economical DC process.

Acknowledgements This work was supported by a grant from Eli Lilly and Company through the Lilly Research Award W-J. Sun is grateful to the Department of Pharmaceutics, University of Minnesota for a

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Program.

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David and Marilyn Grant Fellowship in Physical Pharmacy (2015-2017) and the Dane O. Kildsig

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Center for Pharmaceutical Processing Research (CPPR) for partial financial support. References

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(2012) 4258-4266. [17] S.R. Perumalla, S. Paul, C.C. Sun, Enabling the tablet product development of 5-fluorocytosine by conjugate acid base cocrystals, J. Pharm. Sci., 105 (2016) 1960-1966. [18] Neusilin - The Specialty Excipient, Fuji Chemical Industry Co., Ltd, (2009). [19] W.-J. Sun, A. Aburub, C.C. Sun, Particle engineering for enabling a formulation platform suitable for manufacturing low-dose tablets by direct compression, J. Pharm. Sci., 106 (2017) 1772-1777. [20] L. Shi, C.C. Sun, Transforming powder mechanical properties by core/shell structure: compressible sand, J. Pharm. Sci., 99 (2010) 4458-4462.

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[29] C. Wang, S. Hu, C.C. Sun, Expedited development of diphenhydramine orally disintegrating tablet through integrated crystal and particle engineering, Mol. Pharm., 14 (2017) 3399-3408. [30] C.C. Sun, H. Hou, P. Gao, C. Ma, C. Medina, F.J. Alvarez, H. Hou, P. Gao, Development of a high drug load tablet formulation based on assessment of powder manufacturability: Moving towards quality by design, J. Pharm. Sci., 98 (2009) 239-247.

ACCEPTED MANUSCRIPT Figure 1. Flowability of HPMC with 1.67% silica as a function of comilling cycles at 1 kPa preshear normal stress (n=3). Avicel PH102 serves as a reference material in assessing the suitability of the powders for high speed tableting.

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Figure 2. Scanning electron microscope images of drug-Neusilin composite. (a/b) Neusilin S1; (c/d) NIC-Neusilin composite; (e/f) APAP-Neusilin composite; (g/h) CEL-Neusilin composite. (Left column: 100x magnification, right column: 1000x magnification)

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Figure 3. Characterization of Neusilin, model drugs, and drug-Neusilin composites (10%, w/w). a) DSC thermograms and b) PXRD patterns

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Figure 4. Properties of drug-Neusilin composites (5% w/w drug) and Neusilin a) Flowability at 1 kPa preshear normal stress (n = 3). The dash line indicates the ffc of Avicel PH102. b) Tablet tensile strength at 100 MPa compaction pressure (n = 6).

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Figure 5. Content uniformity of tablets, a) CEL-Neusilin composite at different drug loadings. Tablets of physical mixture are used as references. b) different model drugs at 0.1% drug loading

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Figure 6. Manufacturability of composite-based formulations containing different model drugs (1.0% drug loading and 30% HPMC). a) flowability, b) tabletability, and c) friability

CE

PT

Figure 7. Drug dissolution rate of drug-Neusilin tablets under sink condition (n = 3). a) different model drugs (30% HPMC and 1.0 % drug loading), and b) different amounts of HPMC in the APAP tablets.

AC

Figure 8. Manufacturability of SR formulation containing nanocoated HPMC. a) flowability at 1 kPa preshear normal stress. The dash line indicates ffc of Avicel PH102. b) tabletability

ACCEPTED MANUSCRIPT Table 1. Solution concentration for preparing various drug loadings in the composite powders. Drug content in drug-carrier composite (w/w)

5.26%

5.0%

0.50%

0.5%

0.05%

0.05%

CR

IP

T

Conc. of drug solution (w/v)

US

Table 2. Composition of the platform DC SR tablet formulation

AN

Percentage (%)

Drug - Neusilin composite

M

Hydroxypropyl methylcellulose Microcrystalline cellulose

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Lactose monohydrate Colloidal silica

PT

Magnesium stearate Total

20.0 30.0a 30.0b 19.0b 0.5 0.5 100%

amount can vary to adjust dissolution rate.

b

can be adjusted to accommodate the actual amount of HPMC in the final tablet formulation

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CE

a

Table 3. Effects of amount nano-coated HPMC on various dissolution parameters. 0% HPMC

15% HPMC

30% HPMC

60% HPMC

MDT (hr)

0.05

0.85

2.01

3.23

AUC (hr*%)

1204.4

1133.3

998.0

840.4

T50% (hr)

0.03

0.43

1.24

2.44

ACCEPTED MANUSCRIPT Highlights Good drug content uniformity achieved by loading drug to a porous carrier



Manufacturability is insensitive to drug loading and release controlling polymer



A wide range of drug dissolution is achieved by adjusting amount of HPMC

AC

CE

PT

ED

M

AN

US

CR

IP

T



Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8