physicochemical and release properties of ibuprofen

West African Journal of Pharmacy (2019) 30 (1)

West African Journal of Pharmacy (2019) 30 (1) 119 - 133

119

Physicochemical and release properties of ibuprofen formulations prepared with two native starches and different processing techniques

John O. Ayorinde, Michael A. OdeniyiDepartment of Pharmaceutics and Industrial Pharmacy, University of Ibadan, Nigeria.

Corresponding author: John O AyorindeEmai Phone +234 8053213650l: [email protected]

ABSTRACTBackground: Milling and mixing are unit operations that are often employed in drug formulation.

Objective: This study aims at investigating the physicochemical and release properties of drug formulations containing ibuprofen and different polymers prepared with different milling techniques and freeze-drying.

Methods: Acha rice starch (ACS) and Ofada rice starch (OFS) were extracted from grains of Digitaria exilis and Oryza glaberrima, respectively. Binary mixtures of ibuprofen and ACS, OFS or Hydroxypropyl methyl cellulose (HPMC) were prepared by physical mixing, ball milling and beads milling. Particles from beads milling were freeze-dried. The formulations were evaluated, using particle size analysis, FT-IR, PXRD, scanning electron microscopy and in-vitro release studies.

Results: All the techniques resulted in particle size reduction in the rank order of Freeze-drying > Beads milling > Ball milling > Physical mixing (p < 0.05). Formulations containing OFS and HPMC attained highest particle size reduction with beads milling, while ball mill resulted in highest size reduction in formulations containing ACS. Increasing starch concentration reduced the crystallinity of ibuprofen. Particles of ACS and OFS were more spherical and aggregating than those of HPMC. Formulations containing OFS exhibited highest drug release (p >0.05) with rank order OFS > ACS > HPMC. Drug release from the starches was higher than from HPMC.

Conclusion: The starches possess better physicochemical properties compared to HPMC. Freeze-drying produces formulations with smallest particle sizes and highest reduction of crystallinity of the API. Ofada rice starch formulations are characterized by the best drug release.

Key words: Milling, Ibuprofen, Starch, Formulations, Particle size

West African Journal of Pharmacy (2019) 30 (1)

West African Journal of Pharmacy (2019) 30 (1) 119 - 133

120

Propriétés physicochimiques et de libération de formulations d'ibuprofène préparées avec deux amidons natifs et différentes techniques de traitement

John O. Ayorinde, Michael A. Odeniyi

Département de pharmaceutique et de pharmacie industrielle, Université d'Ibadan, Nigéria.Auteur de correspondance : John O Ayorinde

Email: [email protected] Téléphone +234 8053213650

RESUMEContexte : La mouture et le mélange sont des opérations unitaires qui sont souvent utilisées dans la formulation de médicaments.

Objectif : Cette étude vise à examiner les propriétés physicochimiques et de libération de formulations de médicaments contenant de l'ibuprofène et différents polymères préparés avec différentes techniques de broyage et de lyophilisation.

Méthodes : L'amidon de riz Acha (ACS) et l'amidon de riz Ofada (OFS) ont été extraits de grains de Digitaria exilis et d'Oryza glaberrima, respectivement. Des mélanges binaires d'ibuprofène et d'ACS, d'OFS ou d'hydroxypropylméthylcellulose (HPMC) ont été préparés par mélange physique, broyage à boulets et broyage à billes. Les particules provenant du broyage des billes ont été lyophilisées. Les formulations ont été évaluées à l'aide d'analyses granulométriques, de spectroscopie FT-IR, de PXRD, de microscopie électronique à balayage et d'études de libération in vitro.

Résultats : Toutes les techniques ont abouti à une réduction de la taille des particules dans l'ordre de classement : lyophilisation> broyage à billes > broyage à boulets> mélange physique (p <0,05). Les formulations contenant OFS et HPMC ont obtenu la réduction de la taille de particule la plus élevée avec le broyage à billes, tandis que le broyage à boulets a entraîné la réduction de la taille la plus élevée dans les formulations contenant de l'ACS. L'augmentation de la concentration en amidon a réduit la cristallinité de l'ibuprofène. Les particules d'ACS et d'OFS étaient plus sphériques et agrégées que celles de HPMC. Les formulations contenant du OFS présentaient la plus forte libération de médicament (p> 0,05) avec le classement par ordre OFS> ACS> HPMC. La libération de médicaments par les amidons était plus élevée que par HPMC.

Conclusion: Les amidons possèdent de meilleures propriétés physicochimiques par rapport à HPMC. La lyophilisation produit des formulations avec les plus petites tailles de particules et une réduction maximale de la cristallinité de l'API. Les formulations d'amidon de riz Ofada sont caractérisées par la meilleure libération de médicament.

Mots-clés : Mouture, Ibuprofène, Amidon, Formulations, Granulométrie

West African Journal of Pharmacy (2019) 30 (1)121

Processing techniques in drug formulation

INTRODUCTIONThe abundance of starch and its usefulness to humans and their ancestors, both as food and otherwise is as old

1as the age. The usefulness of starch is attributable to certain intrinsic properties which include cost,

2 accessibility and being fully biodegradable. In the pharmaceutical industries, starch ranks among the top ten excipients and are applied in drug formulations as fillers, disintegrants, binders, glidants, lubricants or suspending agents due to its suitable physicochemical

3, 4properties and relative inertness. Few materials used in pharmaceuticals exist in the optimum size and hence most materials must be communited during production of a dosage

5form. Therefore, drug manufacturers attempt to reduce the particle size of materials before or during the process of incorporat ion wi th the act ive pharmaceutical ingredient (API) through the operation of milling. Milling could be classified into cutting, compression, impact, attrition or homogenization,

5depending on the mechanism of operation. Milling has been reported as one of the methods whereby the

6properties of native starch could be improved. Mills are equipment designed to impart energy to the materials and effect the desired particle size reduction. A ball mill is an attrition mill, consisting of balls of steel or pebbles, which act as the grinding medium. The balls roll and cascade over one another, thereby communising the materials by the combined effects of

7impacts and attrition.A beads mill consists of a milling chamber and an agitator. The milling chamber is filled with the grinding beads and the material. The agitator discs transmit the energy for grinding to the beads and the size reduction is effected between the grinding beads sliding on each other and/or the vessel sides. Acha rice (Digitalis exilis) also known as fundi, fonio or hungry rice is a cereal indigeneous to West Africa and probably the oldest African cereal. It is one of Nigerian underutilized cereals. Despite its ancient heritage and widespread importance, knowledge of fonio's evolution, origin, distribution, and genetic diversity remains scanty even within West Africa itself. The crop has received just a fraction of the attention accorded to sorghum, millet or maize. The grains are tiny, long

8kernels and the plant can grow in poor sandy soil. Acha rice is produced and consumed locally because the usefulness is not yet properly elucidated. The carbohydrates and physicochemical properties of Acha starch have been investigated to a little extent and its use in pharmaceuticals has not been assessed.Ofada rice is mostly as blends and usually contains

Oryza glaberrima (African rice) as well as the more common Oryza sativa (Asian rice). Ofada rice is unpolished, some or all of the rice bran is left on the grain, strengthening the flavour and making it more nutritious. It is widely consumed in the south west of

9Nigeria, for its taste and nutrients. More than acha rice, ofada rice has been investigated for use in pharmaceuticals. The starch in Ofada rice has been used in pharmaceutical delivery as a sustained release

10polymer in microsphere formulations of repaglinide. This study aims at characterizing Acha rice and Ofada rice starches and comparing their physicochemical and release properties with those of Hydroxypropyl methyl cellulose (HPMC). The effects of different milling techniques and freeze-drying on particle size reduction, morphology and crystallinity in formulations containing different polymers and Ibuprofen will be determined.

METHODSMaterialsThe following materials were used in the work: Ofada rice starch (OFS) obtained from grains of Oryza glaberrima, Acha rice starch (ACS) obtained from grains of Digitaria exilis, Ibuprofen (BASF, Ludwigshafen, Germany), Hydroxypropyl methyl cellulose (HPMC-5.11) obtained from BASF, Ludwigshafen, Germany. All other reagents used were of analytical grade and were used as obtained.

MethodsExtraction of the starchesStarches were extracted from the grains of Oryza glaberrima and Digitaria exilis following established

11, 12extraction procedure. The grains were washed with distilled water and milled, using a domestic blender (Elgento-125, China) and then soaked in distilled water for four days, while the supernatant water was constantly discarded and replaced twice in a day. The extracted starch was dried in the oven for three days at

050 C, after which it was milled and sieved, using a 0.25µm sieve. The starches were stored in air tight containers.

Physicochemical propertiesDensitiesA 10 g quantity of each starch was placed in the TAP Density tester (USP ELECTROLAB ETD-1020) to determine the bulk density, tapped density, Carr's Compressibility index and Hausner's ratio. Standard taps of 250 at USP1 mode was used in determining the tapped density. Particle density (True density) was determined using the True Density Meter (SMART


Ayorinde and Odeniyi

PYCNO 30). All determinations were done in triplicates.

ViscosityA 2% dispersion of starch in water was made and the viscosity was determined at room temperature on a viscometer (Brookfield Viscometer DV2T), spindle 02 was used. Determinations were done in triplicates.

Swelling indexSwelling index of each starch was carried out by weighing 5g into in 100mL measuring cylinder. Volume was made up to 100mL mark with distilled water. The height of powder in the measuring cylinder was taken as h1. Another reading of the height of powder (h2) was taken after 24 hours. Swelling index was calculated as a percentage of the ratio of h2 to h1. Determinations were done in duplicates.

Preparation of formulationsFormulations containing Ibuprofen (IBP) and either Ofada rice starch (OFS), Acha rice starch (ACS) or HPMC were prepared in the ratios 1:2 and 1:3. The following four techniques were used in incorporating the API with the different polymers:

Physical mixingQuantities of the API and polymer in the stated ratios were weighed into a mortar and mixed together with pestle, using geometric dilution method.

Ball millingApproximately 1g of API/polymer blends at each ratio was weighed into the vessel of a ball mill (FRITSCH Pulverisstte Ball Mill) and milling was carried out for 2hours at the speed of 500rpm.

Beads millingMilling of each of the API/polymer blends was carried out, using a beads mill (Ultra Apex Mill UAM 015 Hiroshima Metal & Machinery Co LTD). The milling was carried out at a speed of 3470rpm, feeding rate of 150mL per minute, using 400g of 0.1mm beads.

Freeze-dryingSlurry obtained from the beads mill was subjected to

0freeze-drying for 2 hours at a temperature of -50 C on EYELA PFR 1000. The particles obtained were dried on EYELA FDU 830, for 3 days and stored for further investigations.The formulation codes, constituents of different formulations and the incorporation techniques used are contained in Table 1.

Solid state characterizationParticles obtained from the processes of physical mixing, ball milling, beads milling and freeze-drying were characterized by:(a). Particle size analysisEach starch sample was first dispersed in Smith's starch reagent to prevent swelling before analysis. Analysis of the particle size was carried out using a laser diffraction based apparatus equipped with a dry dispersion system (MT3300EXII MicrotracBEL, Corp., Osaka, Japan). The equipment has a detection rate of 0.02 to 2000µm and a pressure of 0.20MPa was used. The particle size and size distribution of the polymers were determined at D10, D50 and D90. Span of size distribution was also calculated according to the equation:Span = (D90 – D10)/D50....................................(1).Determinations were done in triplicates.

(b). Powder X-ray diffractometry The powder Xray diffraction was carried out on a powder X-ray diffractometer (RigakuMiniflex 600, Tokyo, Japan) under the following conditions: a slit-detector Cu Kα radiation source

(30kV, 15mA, λ = 0.15418nm), 2ɵ scan range was 3-350

and a scan rate of 40/min under ambient temperature.

(c). FT-IR spectroscopyInteraction between the starches and API was studied using the Fourier transform infrared spectroscopy (FT-IR). Spectra of ibuprofen, plain starches and the formulations were recorded on the FT-IR spectroscope (Model 2000 Perkin Elmer Spectroscopy, USA apparatus). Samples were prepared in KBr discs

-1(1%w/w). A scanning range of 1000 - 4500cm was used.

(d). Analysis of surface morphologySamples of the starch was placed on the metallic stub and sputtered with thin layer of gold in a vacuum in order to make it electron conductive. The sample was placed in a Scanning Electron Microscope (Hitachi Japan, model S3400N. 7) for determination of surface morphology. Images of the samples were taken at 100X, 200X, 300X, 500X and 1000X magnifications.

In-vitro drug releaseTo study the release of API from formulations containing the polymers, the in-vitro release of ibuprofen from the formulations prepared by freeze-drying was determined using a six-station dissolution apparatus (DBK Instrument, England). The dissolution


medium used was 900 mL of phosphate buffer, pH 6.8. Conditions of a bath temperature, 37±2°C and a basket rotation, 100 rpm, paddle method were maintained throughout the test period. Formulation containing 100 mg Ibuprofen was dispersed in each basket. Samples of 5mL each were withdrawn from the dissolution medium at 0, 5, 10, 15 and 30 minutes, then at 1 h interval for 8 h. After every withdrawal, a fresh 5 mL phosphate buffer solution was used to replace the withdrawn sample. The samples withdrawn were filtered through a 0.45 µm membrane filter and then the drug content was determined on a UV-Visible spectrophotometer (CECIL CE7400S, ENGLAND) at a wavelength of 232 nm. Determinations were made in duplicates for each formulation.

Mechanism of drug releaseTo study the mechanism of release of the API from the formulations, the drug release data were analyzed using zero order kinetic, first order kinetic, Higuchi model, Hixon-Crowwell and Korsemeyer-Peppas equations. The constants of release kinetic and coefficient of correlation (r2) were obtained from slopes of linear regression plots. In order to determine the mechanism of drug release, the release data was

13, 14fitted into the Korsemeyer-Peppas equation: Log (Mt/Mf) = Log k + nLog t ....................................(2)Mt is the amount of drug release at time t, Mf is the amount of drug release after infinite time; k is a release rate constant incorporating the structural and geometric characteristics of the dosage form and n is the diffusion exponent, which indicates the mechanism of drug release. The equation was used to characterize drug release rate from the dosage form and the retarding efficiency of the polymer. Values of MDT were calculated from dissolution data using the equation:MDT = (n/n + 1)k – 1/n .................................(3)Where n is the release exponent and k is release rate

constant.

Statistical analysisThe data obtained were analysed statistically using ANOVA, followed by posthoc Turley's test in cases where more than two sets of data were obtained, in order to determine the level of significance (p-values) of an effect or the difference between means. Significance at 95% confidence was considered significant or different at p = 0.05.

RESULTSPhysicochemical propertiesRe s u l t s o f d e n s i t y m e a s u re m e nt s , C a r r ' s compressibility index, Hausner's ratio, swelling index and viscosity determinations are presented in Table 2. Ranking order for bulk and tapped densities was ACS > HPMC > OFS. The starches showed better water absorption capacity and viscosity than HPMC.

Particle size of the starchesEffects of the Polymers and Milling Techniques on Particle Size of APIThe effects of different polymers and milling techniques on the material properties and particle size of the formulations are presented in Table 3. Incorporation of the polymers to ibuprofen resulted in reduction of particle size; formulations containing ACS had the smallest particle size. All the techniques used in incorporating the API with the polymers resulted in reduction of particle size. Ball milling produced formulations of smaller particle size than physical mixing, while beads milling resulted in formulations with smallest particle size. Formulations containing HPMC and OFS had its least particle size when beads milling was used while there was no significant difference between the particle sizes of formulations containing ACS when different milling techniques were used.



Table 1. Formulation codes, constituents of the formulations and incorporation technique.

Formula tion Code

Constituents API:Polymer ratio Incorporation technique

OPM2 Ibuprofen and Ofada rice starch 1:2 Physical Mixing

OPM3 Ibuprofen and Ofada rice starch 1:3 Physical Mixing

APM2 Ibuprofen and Acha rice starch 1:2 Physical Mixing

APM3 Ibuprofen an d Acha rice starch 1:3 Physical Mixing

HPM2 Ibuprofen and HPMC 1:2 Physical Mixing HPM3 Ibuprofen and HPMC 1:3 Physical Mixing

OBM2 Ibuprofen and Ofada rice starch 1:2 Ball Milling

OBM3 Ibuprofen and Ofada rice starch 1:3 Ball Milling

ABM2 Ibuprofen a nd Acha rice starch 1:2 Ball Milling

ABM3 Ibuprofen and Acha rice starch 1:3 Ball Milling

HBM2 Ibuprofen and HPMC 1:2 Ball Milling

HBM3 Ibuprofen and HPMC 1:3 Ball Milling

OBD2 Ibuprofen and Ofada rice starch 1:2 Beads Milling

OBD3 Ibuprofen and Ofada rice starch 1:3 Beads Milling ABD2 Ibuprofen and Acha rice starch 1:2 Beads Milling

ABD3 Ibuprofen and Acha rice starch 1:3 Beads Milling

HBD2 Ibuprofen and HPMC 1:2 Beads Milling

HBD3 Ibuprofen and HPMC 1:3 Beads Milling

OFD2 Ibuprofen and Ofada ric e starch 1:2 Freeze -drying

OFD3 Ibuprofen and Ofada rice starch 1:3 Freeze -drying

AFD2 Ibuprofen and Acha rice starch 1:2 Freeze -drying

AFD3 Ibuprofen and Acha rice starch 1:3 Freeze -drying

HFD2 Ibuprofen and HPMC 1:2 Freeze -drying

HFD3 Ibuprofen and HPMC 1:3 Freeze -drying

Table 2. Physicochemical properties of the polymers (mean± s.d.)

Parameters OFS ACS HPMC

Bulk density (g/cm3) 0.31± 0.25 0.20 ± 0.75 0.24 ± 0.66

Tapped density (g/cm 3) 0.57± 0.30 0.47 ± 0.35 0.51 ± 0.75

Particle density (g/cm 3) 1.49± 0.55 1.51± 0.55 1.48 ± 0.35

Carr’s Index (%) 45.61± 0.75 57.44 ± 0.85 52.94 ± 0.75

Hausner’s Ratio 1.84 ± 0.33 2.35 ± 0.55 2.13 ± 0.25

Swelling Index (%) 70.00± 1.00 60.00± 0.85 20.00 ± 1.05

Viscosity (mPa.s) 15.00± 1.25 13.80± 1.20 3.00 ± 1.40



Table 3. Particle size distribution of formulations obtained prepared with different techniques (mean± s.d.)

Formulation D10(µm) D50(µm) D90(µm) Span

OPM2 7.92 ± 2.85 27.58 ± 1.95 86.66 ± 5.50 2.85

OPM3 7.99 ± 1.22 28.72 ± 2.20 91.28 ± 1.75 2.90

APM 2 6.89 ± 2.55 13.77 ± 1.85 56.41 ± 3.55 3.59

APM3 7.02 ± 4.78 14.12 ± 1.77 60.28 ± 2.85 3.77

HPM2 22.15 ±1.92 46.34 ± 2.88 98.09 ± 2.20 1.64

HPM3 22.99 ± 1.95 48.17 ± 3.95 326.10 ± 5.50 6.29

OBM2 7.37 ± 4.55 20.15 ± 3.35 53.60 ±6.50 2.29

OBM3 6.95 ± 6 .50 20.26 ± 4.50 63.22 ± 4.52 2.78

ABM2 6.79 ±2.52 10.13 ± 3.55 16.22 ± 3.51 0.93

ABM3 6.29 ± 1.22 9.62 ± 7.50 16.55 ± 2.55 1.07

HBM2 6.02 ± 1.50 20.38 ± 5.75 52.02 ± 4.50 2.26

HBM3 5.62 ± 1.55 19.99 ± 7.20 46.25 ± 3.50 2.26

OBD2 2.10 ± 1.50 7.73 ± 2. 50 39.12 ± 7.55 4.79

OBD3 4.36 ± 1.20 7.68 ± 2.52 13.59 ±3.22 1.20

ABD2 3.80 ± 1.55 11.58 ± 5.85 22.72 ± 6.52 1.63

ABD3 7.81 ± 2.28 10.33 ± 5.80 14.54 ± 4.55 0.65

HBD2 0.17 ± 3.75 10.14 ± 7.52 58.26 ± 5.60 5.73

HBD3 1.20 ± 1.85 9.75 ± 6.55 15.65 ± 6.6 5 1.48

OFD2 6.22 ± 2.55 21.43 ± 7.15 86.44 ± 8.25 3.74

OFD3 5.03 ± 4.55 8.58 ± 7.20 21.81 ± 7.25 1.96

AFD2 6.10 ± 3.53 20.73 ± 6.52 61.32 ± 6.22 2.66

AFD3 7.56 ± 6.55 11.79 ± 6.42 28.45 ± 4.50 1.77

HFD2 3.73 ±1.20 14.19 ± 2.55 45.15 ± 3.25 2.92

HFD3 1.99 ± 2.01 14.13 ± 5.75 57.25 ± 4.50 3.92

Drug-polymer interactionThe FT-IR spectra of the formulations and Ibuprofen (Fig. 1) showed that there was no observable alteration in the functional group of the API as a result of polymer interaction.Powder X-ray diffractograms (Fig. 2a) showed that formulations obtained from freeze-drying was most amorphous, with the rank order OFD3 > OBD3 > OBM3

>OPM3. The same trend was observed in formulations containing ACS (Fig. 2b).The surface morphology study by scanning electron microscopy (Fig. 3a-c) revealed that ACS and OFS to be more spherical and aggregating than HPMC. The SEM images in Figure 3d-f showed that ball and beads milling resulted in formulations with more spherical, rough and aggregating appearance than physical mixing.



Fig 1. FT-IR Spectra of API, starches, and formulations containing the starches and API

Fig 2a. PXRD of API, OFS and API/OFS Formulations (1:3) prepared, using different techniques



Fig 2b. PXRD of API, ACS and API/ACS Formulations (1:3) prepared, using different techniques

Fig. 3a. SEM Image of HPMC Fig. 3b. SEM Image of ACS



Fig.3c: SEM Image of OFS Fig. 3d: SEM Image of formulation prepared by physical mixing

Fig. 3e: SEM Image of formulation prepared by ball milling

Fig. 3f: SEM Image of formulation prepared by beads milling

Release properties of the formulationsThe release profiles of the formulations prepared by freeze dried materials are shown in Figure 4. There was a slow release over the first 30 minutes, then a burst in all the formulations at 1hour. The release was steady and increased until the sixth hour.

The results in Table 5 suggest that formulations containing Ofada rice and Acha rice starches gave better drug release potentials than HPMC formulations and at t , the percentage drug release from the starches was 90

higher than from HPMC.



Table 4. Model independent dissolution parameters for the formulations

Formulation

Code

t25% (h) t50% (h) t75% (h) t90%(h) MDT (h)

F2FD 6.22 25.29 57.47 83.12 4.29

F3FD 5.26 21.13 47.66 68.72 1.69

F6FD 5.5 7 21.14 46.11 65.47 1.00

F7FD 4.47 17.09 37.42 53.23 1.51

F10FD 2.96 14.20 35.57 53.76 11.50

F11FD 3.02 14.62 36.75 55.62 8.59

Table 5. In vitro release kinetics for formulations

Formulation code

Zero-order First-order Higuchi Hixson-Crowell Korsemeyer-Peppas

r2 k0 r2 k1 r2 KH r2 KHC N r2 K

F2FD 0.491 18.429 0.799 0.301 0.941 31.461 0.717 0.086 0.494 0.941 31.614

F3FD 0.489 20.138 0.826 0.354 0.915 34.393 0.742 0.099 0.498 0.915 34.444

F6FD 0.557 20.243 0.853 0.354 0.914 34.431 0.781 0.099 0.520 0.915 33.876

F7FD 0.572 22.599 0.912 0.434 0.946 38.436 0.839 0.120 0.517 0.947 37.899

F10FD 0.252 23.644 0.830 0.508 0.914 40.878 0.702 0.137 0.442 0.927 42.824

F11FD

0.250 23.336 0.836 0.491 0.939 40.331 0.704 0.132 0.440 0.953 42.311

Fig.4. Ibuprofen release from formulations containing different polymers, prepared by freeze-drying technique



DISCUSSIONThe starches had similar results for bulk and tapped densities with HPMC. Ranking order for bulk and tapped densities was OFS > HPMC > ACS (p>0.05). This is an indication that the starches have similar cohesiveness with HPMC. Packing and cohesive properties are important parameters in powder mixing and filling in

15 both capsule and tablet production. Particle density is the true density of materials, obtained after the entire void is removed. Similar values of particle density were obtained for OFS, ACS and HPMC (p>0.05), which suggests that the starches also have similar packing characteristics with HPMC.The ranking for both Hausner's ratio and Carr's compressibility index (Table 2) is OFS > HPMC > ACS. The values for these two parameters were similar for the three polymers. However, ACS and HPMC had similar values, while OFS has the lowest value among the polymers. Carrs' index and Hausner's ratio are indirect measures of determining fluidity and low values

11indicate good flow. These results therefore indicate that the starches have comparable flow and compaction characteristics with HPMC. However, OFS appeared to show better flow and higher tendency to form a compact upon application of compression force than ACS and HPMC.The starches have higher swelling capacity compared to HPMC (Table 2) with the rank order as OFS > ACS > HPMC (p<0.05). Swelling index is an indication of the water absorption capacity of a material. It is controlled by two forces; the free energy of mixing, by which the solvent penetrate and then dilute the material and the elastic retractile force, by which deformation is opposed. A material reaches a steady swelling state

16,17when there is a balance between the two forces. Results indicated that HPMC reached the steady state faster than the starches.The starches presented with higher viscosity than HPMC. Viscosity measures the resistance to flow at a particular shear or tensile stress. High value of viscosity indicates high resistance to flow due to high internal

17, 18friction; the more viscous a material is, the more the force that is needed to produce flow. The high viscosity and water absorption properties of the starches confer good potential for use in producing delayed release dosage forms.Interaction between the polymers and ibuprofen resulted in reduction of particle size of Ibuprofen in the formulations (Table 3); formulations containing ACS had the highest reduction (p<0.05). The particle size reduction suggests the starches can evenly disperse the API and reduce its particle size in the formulations.

Furthermore, increasing the concentration of polymers from 1:2 to 1:3 in the formulation resulted in significant

19increase in particle size reduction. Patel et al. (2006) reported that the higher the concentration of polymers, the more amorphous the dispersed API becomes. Generally, all the techniques used in mixing the polymers and API resulted in reduction of particle size (Table 3). However, ball milling produced formulations of smaller particle size than physical mixing, while beads milling resulted in formulations with least particle size. A ball mill consists of a rotating hollow vessel of cylindrical shape. The mill is partially filled with balls of pebbles which act as grinding medium. The balls roll and cascade over one another and the material via

7the mechanisms of impact and attrition. In the case of a beads mill, the dispersion system consists of a milling chamber and an agitator; the energy for dispersion and grinding is transmitted to the grinding beads by the agitator discs. The dispersion process takes place between the grinding beads sliding on each other and between the rotor and/or the vessel and the beads thereby resulting in modification of the starch particle

6, 20size.Formulations containing HPMC and OFS had the least particle size when beads milling was used; the difference in particle size with other techniques was significant. This suggests that a sophisticated milling technique is required to achieve optimum size reduction with HPMC and OFS. On the other hand, there was no significant difference between the particle sizes of formulations containing ACS when different milling techniques were used; this indicates that the simplest method of milling is capable of producing optimum size reduction with ACS. This is particularly important in small scale industries and developing countries where sophisticated milling equipments may not be available.The time employed in milling process also had different effects on the particle size reduction obtained in the formulations. There was significant difference in particle size of HPMC formulations when time of ball milling increased from one to two hours, whereas the time of milling did not produced any significant effect in the formulations containing the starches. This could be an advantage because maximum size reduction is obtainable in a short period of time. The possibility of any change in the functional groups due to interaction between the polymers and API was the purpose of the FT-IR spectroscopy (Figure 1). There was no observable alteration in the functional group of the API. The bands shown by the plain API and formulations were similar with no distinct peak which


21 - suggests that the API and the starches are compatible.23 The characteristic crystalline peaks of Ibuprofen was

observed with peaks at 2ɵ of 5, 12, 17, 20, 23 and 25

while the starch was shown to have halo band of 14,23amorphous materials (Figure 2). The halo bands

show increase in the amorphous nature with increasing concentration of OFS in the formulations. ACS produced greater reduction of crystallinity than either OFS or HPMC.Formulations obtained from freeze-drying was most amorphous, with the rank order F3FD > F3BMb > F3BMa > F3PM (Figure 2). The results suggest that freeze-drying produced formulations with highest solubility; this is attributable to possible increase in surface area which resulted from freeze-drying and milling processes. Beads milling have been reported to

24be capable of producing amorphous particles.From the scanning electron microscopy, ACS and OFS appeared more spherical and aggregating than HPMC (Fig. 3a-c). This suggests possibility of bond formation and spatial network with the starch particles which can result in bioadhesion; a feature that has been found

25, 26useful in sustained release action in drug delivery. Furthermore, the starches had rough appearance

27which is an indication of amorphous nature. Surface morphology of OFS formulations prepared by different techniques (Fig. 3d-f) showed that ball and beads milling produced formulations which appear more spherical, rough and aggregating than physical mixing.The characteristic slow release over the first 30 minutes, the burst in all the formulations at 1hour and the steady release until the sixth hour indicate that the formulations can sustain release of the API for six hours. The dissolution parameters show that at t , 90

formulations containing Ofada rice starch and Acha rice starch gave high drug release of 83.12 and 65.47%, respectively (Table 4). The rank order for drug release among the formulations was F2FD > F6FD > F10FD (p >0.05). This suggests that formulations containing Ofada and Acha rice starches gave better drug release than HPMC formulations and have the potential of providing optimum bioavailability from the drug formulations. The mechanism of drug release studied by fitting the release data into various mathematical models of zero order kinetic, first order kinetic, Higuchi model, Hixson-Crowell and Korsemeyer-Peppas produced the

2coefficient of correlation (r ) and N values (Table 5). Korsemeyer-Peppas model is suitable for describing the

13mechanism of drug release from polymeric systems. In

Korsemeyer-Peppas equation, a value of N which is 0.43 or less indicates that the mechanism of release is by diffusion and it is termed Fickian (case I) release. When N is 0.85, the mechanism of release is swelling controlled; this is termed super case II release while when N has a value between 0.43 and 0.85, the mechanism of release is by both diffusion and swelling controlled; a condition that is termed non-Fickian

28(anomalous) release. The values of N in all the formulations are between 0.43 and 0.85 (Table 5). This indicates that the mechanisms of drug release were both by diffusion and swelling controlled. All the

2 formulations had the highest value of r in Korsemeyer-Peppas equation. This indicates that the drug release was not dependent on the polymer concentrations, which explains why a higher drug release was obtained from formulations of API:Polymer ratio of 1:2 than formulations containing polymers at higher concentrations. Other processing techniques involved in tabletting could be evaluated in further studies.

CONCLUSIONAcha rice and Ofada rice starches showed similar physicochemical properties with HPMC. The milling techniques and nature of polymer used in the formulations had effects on the particle size and crystallinity of the API. Formulations produced with beads milling and freeze-drying techniques are characterized by the smallest particle size and highest reduction of crystallinity of ibuprofen. Formulations containing Acha rice starch are characterized by smaller particle size and more amorphous characteristics, compared to Ofada rice starch and HPMC. The starches are characterized by better release profile compared to HPMC; Ofada rice starch possesses the best drug release property compared to the other polymers. Acha rice, which hitherto has little relevance, could be a source of useful pharmaceutical excipient, just like Ofada rice, and cultivation of these cereals will be further encouraged if the use is extended to production of pharmaceutical excipients.

ACKNOWLEDGEMENTThe authors hereby acknowledge the following:1. Matsumae International Foundation (MIF), Japan; for the award of research fellowship, for the period which this work was carried out in Japan.2. Professor Yuichi Tozuka, Osaka University of Pharmaceutical Sciences, Japan; for being my Host Professor in Japan and for using his laboratory for this work.



REFERENCES1. Builder PF, Arhewoh MI (2016). Pharmaceutical

applications of native starch in conventional drug delivery. Starch 68: 864 - 873

2. Luo Z, Zhou Z (2012). Homogeneous synthesis and characterization of starch acetates in ionic liquid without catalysts. Starch 64: 37 - 44

3. Preetha B, Pandit JK, Rao VU, Bindu K, Rajesh YV, Balasubramaniam J (2008). Comparative Evaluation of Mode of Incorporation of Superdisintegrants on Dissolution of Model drugs from wet granulated tablets. Acta Pharmaceutica Sciencia 50: 229 - 236

4. Odeniyi MA, Atolagbe FM, Aina OO, Adetunji OA (2011). Evaluation of mucoadhesive properties of native and modified starches of the root tubers of cocoyam (Xanthosoma sagittifolium). African Journal of Biomedical Research 14: 169-174

5. Khar, Roop K.; Vyas,S.P.; Ahmad, Farhan J.; Jain, Gaurav K (2013), eds. The Theory and Practice of Industrial Pharmacy. New Delhi, India, pp.31 - 64.

6. Hu H, Liu W, Shi J, Huang Z, Zhang Y, Huang A, Yang M, Qin X, Shen F (2016). Structure and Functional Properties of Octenyl Succinate Anhydride Modified Starch Prepared by a Non-conventional Technology. Starch-Starke 68: 151 - 159.

7. Takacs L (2002). Self sustaining reactions induced by ball milling. Progress in Material Science 47:355 - 414. DOI: 10.1016/S0079-6425(01)00002-0.

8. Koreissi-Dembele Y, Fanou-Fogny N, Hulshof P, Brouwer I (2013). Fonio (Digitalis exilis) landraces: Nutrient and phytate content, genetic diversity and effect of processing. J Food Composition and Analysis 29(2): 134 - 143.

9. Gyimah-Brempong K, Johnson M, Takeshima H (2016). The Nigerian Rice Economy: Policy Option for Transforming Production, Marketing and Trade. University of Pennsylvania Press: Nigeria, pp.30 - 31.

10. Okunlola A, Owojori T (2016). Impact of degree of substitution of acetylated Ofada rice starch polymer on the release properties of nimesulide microspheres. Journal of excipients and food chemicals 7(1): 4-16.

11. Riley CK, Adebayo SA, Wheatley AO, Asemota HN (2008). The Interplay between yam (Diosorea sp.) starch botanical source, micromeritic properties and their functionality in paracetamol granules for reconstitution. Eur J Pharm Biopharm 70: 326-334

12. Ayorinde JO, Odeniyi MA, Oyeniyi YJ (2013). Material and compression properties of native and modified plantain starches. Farmacia 61(3):

574 - 590.13. Dash S, Murthy PN, Nath L, Chowdhuri P (2010).

Kinetic modeling on drug release from controlled drug delivery systems. Act Pol Pharm-Drug Res 67(130): 217-223.

14. Ayorinde JO, Odeniyi MA (2017). Solid state characterization of two novel plant gums from Cedrela odorata and Enterolobium cyclocarpum. Journal of Pharmaceutical Investigation DOI: 10.1007/s40005-017-0343-7.

15. Cain J (2002). An alternative technique for determining ANSI/CEMA standard 550 flowability ratings for granular materials. Powder Hand Proc 14(3): 218-220.

16. Franceschini F, Selmin S, Monghetti F, Cilurzo F (2016). Nanofiller for mechanical reinforcement of maltodextrin orodispersible films. Carbohydr Polym 135: 676-681.

17. Ayorinde JO, Odeniyi MA (2016). Material and compression properties of native and co-processed breadfruit starches. Nig J Pharm Res 12: 21 - 29.

18. Sanchez L, TorradoS, Lastres JL (1995). Gelatinized/freezdried starch as excipient in sustained release tablet. International Journal of Pharmaceutics 115: 201-208.

19. Patel A, Ray S, Thakur RS (2006). In-vitro evaluation and optimization of controlled release floating drug delivery system of metformin hydrochloride. DARU 14: 57- 64.

20. Fuchs J, Feldmann M, Abmann C, Vorwerg W, Heim HP (2018). Cross-Linked Hydrophobic Starch Granules in Blends with PLA. International Polymer Processing 33: 89 - 95.

21. Odeniyi MA, Khan NK, Peh KK (2015). Release and mucoadhesion properties of diclofenac matrix tablets from natural and synthetic polymer blends. Act Pol Pharm Drug Res 72: 559 - 567.

22. Kadota K, Senda A, Tagishi H, Ayorinde JO, Tozuka Y (2017). Evaluation of highly branched cyclic dextrin in inhalable particles of combined antibiotics for the pulmonary delivery of anti-tuberculosis drugs. International Journal of Pharmaceutics 517: 8 - 18.

23. Tiwari M, Chawla G, Bansal AK (2007). Quantification of olanzapine polymorphs using powder X-ray diffraction technique. J Pharm Biomed Anal 43(3): 865-872.

24. Li X, Vogt FG, Hayes Jr. D, Mansour HM (2014). Design, characterization, and aerosol dispersion performance modeling of advanced co-spray dried antibiotics with mannitol as respirable



microparticles/nanoparticles for targeted pulmonary delivery as dry powder inhalers. J. Pharm Sci 103: 2937- 2949.

25. Shaikh AM, Sayyed N, Shaikh S, Patel MS, Chavda AW (2011). Euphobia neriifolia LINN: a phytopharmacological review. Int Res J Pharm 2(5): 41-48.

26. Banarjee P, Deb J, Roy A, Ghosh A, Chakraborty P (2012). Fabrication and development of pectin microsphere of metformin hydrochloride. ISRN

Pharmaceutics doi:10.5402/2012/230621.27. Shah B, Kakumanu VK, Bansal AK (2006). Analytical

t e c h n i q u e s f o r q u a n t i f i c a t i o n o f amporphous/crystalline phases in pharmaceutical solids. J Pharm Sci 95(8): 1641 - 1665.

28. Szekalska M, Winnicka K, Czajkowska-Koanik A, Sosnowska K, Amelian A (2015). Evaluation of alginate microspheres with metronidazole obtained by spray drying technique. Act Pol Pharm Drg Res 72(3): 569-578.



physicochemical and release properties of ibuprofen

Documents