1. INTRODUCTION:

Introduction to Quality by Design:

Quality by Design (QbD) is progressively developing as improvement of the quality of the product through its life succession.¹

Novel Drug Delivery Systems:

The drug delivery is a technique in which we can control the release of API for the therapeutic effect and also advantageous for the product efficiency and compliance.³

Figure 1: Various Routes of Drug Administration by Novel Drug Delivery System⁴

Introduction to Microsponge Drug Delivery System:

With the help of Microsponge in the TDS we can give drug from oral delivery by using bioerodible polymer for the colon site specific delivery which may improve patient passivity because of its site specific drug delivery.^5,6

Figure 2: Photographs of highly porous nature of a microsponge

Microsponges are defined as porous, inert units which is made up of synthetic polymers and act as a shield to the ensnared drug from degradation which can be easily entrapped in the form of creams, lotions, and powders.^[7] In case of Cosmetics and dermatological products, work only at outsided of skin. In the conventional marketed dosage form the active component is present in high concentration and quickly absorbed when apply on the skin.⁸

Method Evaluation Parameters of Microsponges: ^9,10

Various methods are used for the evaluation of the MDS, they are following

· Particle size (Microscopy) Analysis

· Topography of microsponges

· Evaluation of pore structure

· % E.E. and % yield

· Compatibility studies by FT-IR and DSC

· % CDR study

· Kinetics of Drug release

· Other In-vitro studies

Applications of Microsponges¹¹

Table 1: Applications of microsponges

Sl. No.	Active agents	Application
1	Anti-acne (Benzyl peroxide)	Better efficacy with lower skin irritation.
2	Anti-inflammatory (hydrocortisone)	Prolong Action with minimum allergic reaction and dermatomes.
3	Anti-fungal	Sustained release action.
4	Rubefacients	Lower in skin irritancy with reduction in oiliness and odor.

2. MATERIALS AND METHODOLOGY:

2.1. Materials and Equipments Required:

The following materials, chemicals and instruments will be used for Preparation and Characterization of Aceclofenac loaded Microsponges and its subsequent Topical Gel as per Table 2 and 3.

2.1.1. List of Materials:

Table 2: List of Materials:

Materials	Source
Aceclofenac	CAPTAB Pharma. PVT. LTD., Vadodara.
Ethyl cellulose	Astron Research Limited, Ahmadabad.
Eudragit RS 100	Astron Research Limited, Ahmadabad.
PVA	Astron Research Limited, Ahmadabad.
Ethanol	Lobachemi Private Limited, Mumbai.
Liquid Paraffin	Merck Specialties Private Limited, Mumbai.
Petroleum Ether	Merck Specialties Private Limited, Mumbai.
Carbopol 934 P	Ethicare Pharmaceutical PVT. LTD, Por.
Propylene Glycol	Astron Research Limited, Ahmadabad.
Triethanolamine	Astron Research Limited, Ahmadabad.

2.1.2. List of Equipments:

Table 3: List of Instruments:

Equipments	Model and Source
UV-Visible Spectrometer	UV-1700, Shimadzu Corporation.
Mechanical Stirrer	Remi instrument division
Electronic Balance	Ohaus corporation NJ, USA
Humidity Cabinet	Analytical Technologies, Bangalore.
Scanning Electron Microscope	JEOL JSM-6380KVM Oxford Instruments, England
FT-IR Spectrophotometer	Shimadzu Corporation
Compound Microscope	Acculab
Dissolution Apparatus II, USP XXII	Macro scientific works private limited, Delhi.

2.2. METHODOLOGY:

2.2.1. Preformulation of Drug:

To effectively developed the data which are useful to make stable dosage forms that can be mass-produced for manufacturer for that the preformulation study is very useful.

2.2.1.1. Organoleptic Characteristics of Aceclofenac:

The Organoleptic Characteristics of Aceclofenac like color and odor was done by physical examination.

2.2.1.2. Determination of Melting Point of Aceclofenac:

Melting point of Aceclofenac was evaluated by the capillary method.

2.2.1.3. Solubility study of Aceclofenac:

Preformulation solubility analysis was done, which included dissolving the drug with an excess quantity in glass vials containing 20mL suitable solvent system and supernatant solution will be filtered using 0.45μm pore size filter after 24 hrs at room temperature. The first 10 mL of the filtrate was discarded and last portion of the filtrate was suitably diluted with water and assayed spectroscopically at 260nm. The procedure was followed by using different solvents like water, acetone, ethanol, chloroform, ether and pH 7.4 Phosphate buffer.

2.2.1.4. Determination of partition coefficient:

Partition co-efficient of Aceclofenac was determined by: saturating 10ml of n-octanol with 10ml phosphate buffer 7.4 in separating funnel for 24 hours. 10mg of drug added in to separating funnel and intermediate shaking was done for 4 hours. The two solvent layers were separated through separating funnel and the amount of Aceclofenacdissolved in each phase was determined spectrophotomericallyat 275nm against reagent blank prepared in the same manner on a U.V-visible spectrophotometer.

2.2.1.5. Identification and Determination of Wavelength _max (λ_max) of Aceclofenac:

Weigh 100mg of Aceclofenac and dissolved in 100ml methanol. 1ml of this solution was pipette out in separate volumetric flask and diluted with phosphate buffer 7.4 and subjected for UV scanning in the range 200-800 using UV-visible spectrophotometer.

2.2.1.6. Preparation of Calibration Curve for Aceclofenac

2.2.1.6.1. Sample Preparation of stock and standard solutions for Aceclofenac:

Firstly, Accurately Weigh 100mg of Aceclofenac and dissolved in 100mL methanol. 1mL of this solution will be diluted with pH 7.4 phosphate buffer further diluted with phosphate buffer of pH 7.4 to obtain a series of dilutions containing 5, 10, 15, 20 and 25μg of Aceclofenac in 1ml solution. The absorbance of these solutions will be measured at 275nm.

2.2.1.7. Identification of Drug- Aceclofenac by FT-IR Spectroscopy:

By using 1mg of aceclofenac the Potassium bromide IR disc was prepared on the Hydraulic Pellet press which will be scanne of 4000-400 cm^-1re in FTIR and obtained IR Spectrum will be compare with a reference spectrum of Aceclofenac.

2.2.1.8. Drug- Excipients Compatibility Studies by FT-IR:

Potassium bromide IR disc was prepared using Aceclofenac, Ethyl cellulose, Eudragit RS100, PVA, Carbopol 934 and mixture on Hydraulic Pellet press wasscanne 4000-400 cm^-1 region in FTIR and obtained IR Spectrum was compared with a reference spectrum of Aceclofenac.

2.2.1.9. Drug-Excipients Compatibility Studies by DSC:

Thermal analysis of Drug Aceclofenac and polymers was studies employing differential scanning calorimetry which was done to ckeckcompatability for Microsponges formulations.

2.2.1.10. Particle Size Study:

Pure Drug Particle size analysis had done using Optical Microscope and Malvern Instrument.

2.2.2. Formulation and Development of AceclofenacMicrosponges by using QbD Approach:

2.2.2.1. Selection of Formulation and Process Variables by Preliminary Trial Batches of Aceclofenac Microsponges:

To successfully develop the effect of Polymer type, Type of internal phase, type of surfactant, Drug: Polymer ratios on parameters of prepared Microsponges the preliminary trails had been used. AceclofenacMicrosponges were formulated using various Drug: Polymer ratio, Surfactant Concentration, Stirring rate, stirring time, a type of internal phase, Internal phase volume, External phase volume and evaluated for %yield, %E.E. and P.S. for preliminary selection to develop QbD Approach.

2.2.2.2 Selection of Concentration of Retardant Material (Polymer) in Internal Phase:

The varying quantity of drug polymer i.e. 1:1, 1:2 and 1:3 had been used to prepare microsponges and characterized to fix the ratio polymer.

2.2.2.3. Selection of Drug: Polymer Ratio:

The internal phase blank microspongeswas prepare using 20mL internal phases (Acetone) and 50mL of an external phase (Liquid Paraffin) with Polyvinyl alcohol and having a ratio of Drug: polymer 1:1 to 15:1 in the internal phase and minimum concentration will find out.

2.2.2.4. Selection of Internal Phase Type:

For the selection of the internal and the external phases, various investigations was carried out using different internal phase viz. Acetone and Ethanol, with the constant external phases. Various combinations of internal (Acetone and Ethanol) phase was investigated.

2.2.2.5. Selection of Internal Phase Volume:

In order to estimate the effect of varying volume of internal phase, i.e. acetone was assessed using 5mL, 10mL, 15mL and 20mL of the internal phase, but the drug to polymer ratio will be kept constant at 9:1 in 50mL of Liquid paraffin as external phase, stirring speed of 1500 RPM with surfactant concentration of 0.75% w/v of the external phase.

2.2.2.6. Selection of External Phase Volume:

In the external phase volumewe very the volume of external phase, i.e. Liquid paraffin was evaluated using 40mL, 50mL and 60mL of the external phase, but 20mL of acetone as internal phase, stirring speed of 1500 RPM with 0.75% w/v PVA of the external phase were kept constant. The formed Microsponges particles was assessed.

2.2.2.7. Selection of Surfactant Concentration:

The Microspongeswas formulated by changing amount of PVA ranging from 0.5%, 0.75%, 1.0% and 1.25% w/v of the external phase was used and observed for their physical characteristics.

2.2.2.8. Selection of Stirring Speed:

The Microspongeswas formulated at 1000, 1500, 2000 and 2500 RPM while feezing other variables and evaluated for their free drug content and particle size.

2.2.2.9. Selection of Stirring Time

During the manufacturing of microsponges the RPM speed become constant but the stirring time differ i.e. 60 Min, 75 Min and 90 Min while others are keeping all the other variables constant and the formed Microspongeswas evaluated.

2.2.2.10. Selection of Retardant Material (Polymer) in Internal Phase:

The fixed quantity of drug polymer with varying polymer type i.e. Eudragit RS 100, Ethyl Cellulose and Chitosonwas used to prepare microsponges and characterized to fix polymer.

2.2.3. Risk Assessment of Critical Quality Attributes (CQAs) from Preliminary trial Batches to Develop QbD Approach:

Risk assessment is very much useful for the selection of formulation and process variable but it may affect the quality of the product for CQAs by process characterization that defines satisfactory changes in material and process parameters. So as a result we got quality assured product by process design space to develop control strategy. The critical quality attributes are categorized into high, medium and low risk parameters based on knowledge space. Usually high risk parameters are considered important for Design of Experiments as they are having more effect than others and need to be in accepting multivariate ranges.²

2.2.3.1. Characterization of Aceclofenac Microsponges^22,23,24

2.2.3.1.1 Percentage Yield:

It can be calculated by following formula.

Percentage Yield=

Weight of microspheres recovered

---------------------------------------------------------- x 100

Weight (Drug + Polymer )

2.2.3.1.2. Drug Content:

Firstly, weigh accurate amount of 25mg of Microsponges and mix in 25mL methanol with shaking filter this solution using whattman filter paper and withdraw 1mL from this solution to volumetric flask with 10ml dilution in volumetric flask. The quantitative determination of ACF in Microsponges will carried out using a linear model UV absorbance detector at 275nm against blank (methanol).

2.2.3.1.3. Entrapment Efficiency

It can be calculated by following formula.

Drug Encapsulation efficiency =	Actual Drug Content	X 100
	Theoretical Drug Content

2.2.3.1.4. Mean Particle Size Analysis:

Particle size analysis of drug and microspongeswas done using Optical Microscope and Malvern Instrument.

2.2.3.1.5 Topography by SEM

Scanning electron microscopy (SEM) was used to illustrate ultrastructure of prepared Microsponges for morphology and surface topography.

2.2.3.1.6. Differential Scanning Calorimetry

To find the nature & assume interaction of drug and polymer the differential scanning calorimetry is used and the thermal analysis of Aceclofenac loaded Microsponges also find out.

2.2.3.1.7 Solvent Residual Analysis:

Solvent Residual Analysis was done to determine organic solvent residual traces present in microsponges formulation of used as internal phase.

2.2.3.1.8. In Vitro Drug Release Study of Microsponges:

The dissolution test was done in 900mL Phosphate buffer (PH 7.4) at the 37±.5 C, 150 RPM in USP-II Type dissolution apparatus. Aliquots waswithdrawan every hour up to 8 hrs and replaced immediately with fresh solvent. The sample will estimated by absorbance of the solution at λmax 275nm using UV-Visible spectrophotometer. And caluted % CDR.

2.2.3.1.9. Kinetics of Drug Release^24,25

The kinetic release study was performed to find drug release mechanism from dissolution parameter by using different various kinetic model equations.

2.2.3.1.9.1. Zero Order Release Kinetics:

Qt = Q0 + K0t

Where,

Qt = amount of the drug dissolved in time t,

Q0 = initial amount of drug in the solution (most of the times, Q0 = 0) and

K0 = zero order release constant expressed in units of concentration/time.

Plot: Cumulative amount of drug remaining vs time.

2.2.3.1.9.2. First Order Kinetics:

Log C = Log C0 - Kt / 2.303

Where,

C0 = initial concentration of drug,

K = first order rate constant, and

t = time.

Plot: log cumulative percentage of drug remaining vs. time.

2.2.3.1.9.3. Higuchi Model²⁵

Q = KH × t1/2

Where,

KH = Higuchi dissolution constant.

Plot: cumulative percentage drug release vs Square root of time.

2.2.3.1.9.4. Hixson-Crowell Model²⁶

W_O^1/3– W_t^1/3= κ t

Where,

W₀ = initial amount of drug in the pharmaceutical dosage form,

Plot: cube root of drug percentage remaining in matrix vs time.

2.2.3.1.9.5. Korsmeyer-Peppas Model²⁷

Mt / M_∞= k tⁿ

Where,

Mt / M∞ = fraction of drug released at time t,

k = release rate constant and

n = release exponent.

Plot: log cumulative percentage drug release vs log time.

Table 4: Release Kinetic Mechanism

Release Exponent ‘n’	Drug Transport Mechanism	Rate as afunction of Time
0.5	Higuchi Matrix	t^n-0.5
0.5<n<1.0	Non- Fickian Diffusion	t^n-1
1.0	Zero Order Release special Case–II Transport	Zero Order Release
Higher release (n>1)	Super Case–II Transport	t^n-1

3. RESULT AND CONCUSION:

Selection of Formulation and Process Variables by Preliminary Trial Batches of Aceclofenac Microsponges

Table 5: Formulation Design of Trial batches for AceclofenacMicrosponges

Batch	Drug: Polymer Ratio	Type of Internal phase	Volume of Internal Phase (mL)	Volume of Liquid Paraffin (mL)	Surfactant Conc. (%)	Stirring Speed (R.P.M.)	Stirring Time (Mins)
PRELIMINARY SELECTION OF CONCENTRATION OF RETARDENT MATERIALS
TAM1	1:1	Ethanol	10	50	0.75	1500	60
TAM2	1:2	Ethanol	10	50	0.75	1500	60
TAM3	1:3	Ethanol	10	50	0.75	1500	60
PRELIMINARY SELECTION OF DRUG: POLYMER RATIO
TAM4	7:1	Ethanol	10	50	0.75	1500	60
TAM5	9:1	Ethanol	10	50	0.75	1500	60
TAM6	11:1	Ethanol	10	50	0.75	1500	60
TAM7	13:1	Ethanol	10	50	0.75	1500	60
TAM8	15:1	Ethanol	10	50	0.75	1500	60
PRELIMINARY SELECTION OF INTERNAL PHASE
TAM9	11:1	Acetone	10	50	0.75	1500	60
TAM10	11:1	Ethanol	10	50	0.75	1500	60
PRELIMINARY SELECTION OF INTERNAL PHASE VOLUME
TAM11	11:1	Ethanol	5	50	0.75	1500	60
TAM12	11:1	Ethanol	10	50	0.75	1500	60
TAM13	11:1	Ethanol	15	50	0.75	1500	60
TAM14	11:1	Ethanol	20	50	0.75	1500	60
PRELIMINARY SELECTION OF EXTERNAL PHASE VOLUME
TAM15	11:1	Ethanol	10	40	0.75	1500	60
TAM16	11:1	Ethanol	10	50	0.75	1500	60

Selection of Concentration of Retardant Material (Polymer) in Internal Phase

Table 6: Effect of Concentration of Retardant Materials on Batches TAM1 – TAM3

Batch	Yield (%)	Loading Efficiency (%)	Average Particle Size(μm)
TAM1	65.62	79.24	51.38
TAM2	77.83	88.97	67.54
TAM3	79.98	93.32	91.37

Figure 3: Effect of Concentration of Retardant Materials on Batches TAM1 – TAM3

The minimum concentration of the drug polymer ratio is 1:1 because at this concentration, the microsponges showed good physical characteristic like proper shape, size, porosity, particle size distribution and did not collapse even after removal from the solvent and subsequent drying.

Effect Concentration of Retardant Material in the Internal Phase:

For Eudragit RS 100 and EC the polymer material required in the internal phase was found to be 1% W/V. At these concentrations, microsponges formation was initiated and below thisconcentration the microsponges were formed and showed good physical characteristic like proper shape, size, porosity, particle size distribution and did not collapse even after removal from the solvent and subsequent drying.

Selection of Drug: Polymer Ratio

The particle size were found in range from 89.38μm to 46.23μm when the drug to polymer ratio was increased from 7:1 to 15:1. The % E.E. gradually increased upto Drug: Polymer ratio reaches to 15:1 ratio but no further increase in % E.E. Hence, the preparation of microsponges was stopped at the ratio 15: 1.

Table 7: Effect of Drug: Polymer Ratio on Batches TAM4 - TAM8

Batch	Yield (%)	Loading Efficiency (%)	Average Particle Size(μm)
TAM4	75.3	72.64	95.26
TAM5	70.02	79.18	75.52
TAM6	56.53	89.57	35.5
TAM7	80.12	79.33	73.89
TAM8	0	0	0

Figure 4: Effect of Drug: Polymer Ratio on Batches TAM4 - TAM8

Effect of Drug: Polymer Ratio:

The drug to polymer ratio in the internal phase had some effect on the particle size. The mean particle size decreases when the drug to polymer ratio was increased. The encapsulation efficiency and % yield gradually improved with an increase in Drug: Polymer ratio while mean particle size decreased, and the particle size distribution became narrower due to greater viscosity and faster diffusion of the internal phase of the emulsion system.^[51]

Selection of Internal Phase Type

Table 8: Effect of Internal Phase on Batches TAM9 – TAM10

Batch	Yield (%)	Loading efficacy (%)	Avarage Particle Size(μm)
TAM9	88.07	89.59	45.24
TAM10	54.02	80.45	83.29

Figure 5: Effect of Internal Phase on Batches TAM9 – TAM10

Acetone was selected as internal phase as it showed the highest drug entrapment of about 87.16%. The rate of diffusion of this solvent mixture was high when compared to another solvent, thus decreasing the time required for preparation. The drug was found to be freely soluble in acetone providing better entrapment of the drug and imparting good microsponges characteristics.

Effect Selection of Internal Phase:

Acetone was selected as the internal phase as it showed the highest drug entrapment and imparting good microsponges characteristics. The rate of diffusion of this solvent mixture was high when compared to other solvents, thus decreasing the time required for preparation.⁵⁵

Selection of Internal Phase Volume:

The solvent volume affects the particle size greatly due to viscosities of the internal phase. It was found that particle sizes were directly proportionate to viscosity of dispersed phase and hence particle size increases with decreasing volume of solvent used.

Table 9: Effect of Internal Phase Volume Batches TAM11 – TAM14

Batch	Yield (%)	Loading efficacy (%)	Avarage Particle Size(μm)
TAM11	74.28	87.41	45.92
TAM12	69.56	91.43	25.88
TAM13	76.55	79.99	18.35
TAM14	80.15	95.32	59.32

Figure 6: Effect of Internal Phase Volume TAM11 – TAM14

Effect of Internal Phase Volume:

When the amount of acetone was gradually increasing, % E.E. and drug content decreased. This was probably due to the lower concentration of the drug in the high volume of acetone. It was obseved that by reducing Acetone volume, the P.S. of prepared microsponges increases This might be due to the greater viscosity of acetone, the globs of formed emulsion could not be further divided into reduced particles and greater droplets were formed and mean particle sizes increased.⁵¹

Selection of External Phase Volume:

The volume of external phase plays a crucial role in the formation of microsponges with reduction in free drug concentration and particle size. The results of the study show that the particle size ranged from 12μm to 39μm. It was found that 50 mL was the optimum volume necessary.

Table 10: Effect of External Phase Volume on Batches TAM15 – TAM16

Batch	Yield (%)	Loading efficacy (%)	Avarage Particle Size(μm)
TAM15	91.16	85.45	36.29
TAM16	84.47	93.07	13.25
TAM17	72.25	83.38	39.45

Figure 7: Effect of External Phase Volume on Batches TAM15 - TAM16

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Received on 14.04.2021 Modified on 25.04.2021

Res. J. Pharma. Dosage Forms and Tech. 2021; 13(3):185-192.

DOI: 10.52711/0975-4377.2021.00033

Drug Product CQAs	Drug: Polymer Ratio	Volume Of Internal Phase	% Stabilizer Concentration	Agitation Speed
Drug Content	High	Low	Medium	Medium
Entrapment Efficiency	High	Low	High	Medium
Particle Size	High	Medium	High	High
Drug Release	High	Low	Medium	Medium