Formulation and Optimization of Bicalutamide Tablets by using Factorial Design

 

Santanu Roy*, Gurpreet Singh, Naresh Kalra

Faculty of Pharmacy, Lords University, Alwar, Rajasthan, India.

 

ABSTRACT:

The robustness of pharmaceutical dosage forms entails optimizing both the formulation and the level of excipients to obtain the desired quality features. To optimize the formulation in this investigation, a factorial design approach was adopted. For enhancing the dissolution of a Biopharmaceutics Classification (BCS) Class II drug, a two-level four-factor partial factorial design was advocated. Factorial design is a method for systematically determining the relationship between independent process factors and their effect on the response variable. Partial factorial designs were applied in this research work. The particle size distribution of Lactose Anhydrous is used as a dependent variable and Sodium Starch Glycolate (Primojel/Type A) and Magnesium Stearate, Pregelatinised starch (Lycatab)/Anhydrous Lactose/Lactose Anhydrous (Super Tab 21 AN) ratio and the Particle size distribution were used as independent variables for optimization. Response parameters for the final Bicalutamide Tablets 50mg were the percentage of Bicalutamide Tablets 50mg dissolved at thirty minutes. The factorial design models were validated for accurate prediction of response characteristics and used to identify the optimum formulation. Response parameters for final Bicalutamide Tablets 50mg were the percentage of Bicalutamide Tablets 50mg dissolved at thirty minutes. The data were analyzedand response surfaces were generated for tablet percentage of dissolution and content uniformity.

 

 

 

INTRODUCTION: 

Drug substances are barely administered in their original pure state form due to various complications such as taste, stability, proper dose strength, etc. The target dosage form intends to administer a drug at a therapeutic concentration to a particular site of action for a specified period^1-3. Several orally administered drugs have less bioavailability due to their poor water solubility. In the Biopharmaceutics classification system, drugs with decreased aqueous or water solubility, slow dissolution rate, and increased membrane permeability are categorized as Class II drugs^4-5.

 

 

BCS class II drugs, the rate-determining step is a release of the drug from the dosage form and its solubility in the gastric fluid, so increasing the solubility leads to increases in the bioavailability of BCS class II drugs. Dry granulation is one of the many techniques available to enhance drug dissolution and bioavailability of poorly water-soluble drugs^6-7. Bicalutamide, with a half-life of 5.8 days but poorly soluble in water and hence less bioavailable. The super disintegrants used in this study are Sodium Starch Glycolate. Tablets will be prepared by direct compression technique and will be evaluated for uniformity of weight, and dissolution study. The factorial design will be used for the formulation optimization of tablets^8-10.

 

Material and Methods:

Materials:

Bicalutamide was obtained as a gift sample from AARTI Pharma Labs. Anhydrous Lactose (Super Tab 21 AN) (DMV International), Maize Starch (C☆PharmGel) (Univar Solution), Sodium Starch Glycolate (Primojel/Type A) (JRS Pharma), Colloidal Silicone Dioxide (Aerosil 200) (Cabot Sanmar)Talc (Luzenac), Magnesium Stearate (Ferro/Peter Grevens) were used as received.

 

Methods:

The solubility of Bicalutamide in aqueous media as a function of pH was measured and is presented in the below Table. The aqueous solubility of Bicalutamide across the physiological pH range was estimated. The calculated dose solubility volume of Bicalutamide is less than 250ml at pH 1.2 to 4.5 and greater than 250ml at pH 6.0 to 7.8. Bicalutamide is considered a BCS Class II drug (Low Soluble) according to the Biopharmaceutical Classification System (BCS) and details of solubility in different pH levels are summarized below in Table 2.

 

The excipients used in Bicalutamide Tablets 50mg were selected based on the excipient used in the products utilizing the dry granulation process. A summary of the excipient drug substance compatibility studies was assessed through HPLC analysis of binary mixtures of excipient and drug substance at a different ratio depicted in the below table in the solid state. Samples were stored in 10ml amber colour glass vials with low-density polyethylene (LDPE) stoppers and sealed with an aluminum flip-off seal at 40°C/75%RHin close condition. The result the of Drug Substance (Bicalutamide)-Excipient compatibility study is summarized below in Table 3.

 

Dissolution Method:

The release rate of Bicalutamide Tablets 50mg was determined according to the USFDA website, dissolution database using the Dissolution testing Apparatus II (model TDT-60T, Electro lab, India) fitted with paddles. The dissolution test was executed by using 1000 ml of 1% Sodium lauryl sulfate in water kept at 30±0.5℃ and 50rpm.

 

Content Uniformity:

Content Uniformity by Uniformity of Dosage test was carried out by using analytical grade reagents, HPLC (Water make), C18 column, flow rate 2.0min, and gradient method at 275nm using UV detector.

 

Dry Granulation (Slugging) Process for Bicalutamide Tablets 50mg:

The dry granulation (Slugging) process enhances the bulk density of powder at the same time as increasing the particle size, resulting in better-flowing material. Furthermore, bonding the particles of various substances together during the compaction process reduces the inclination to segregate powder particles into different substances which results in an enhancement of the homogeneity of the Bicalutamide within the powder blend, helping an improvement in dissolution. To accomplish good dissolution, a dry granulation (Slugging) process was used for Bicalutamide Tablets 50mg. The detailed composition of the dry granulation process (Slugging) is depicted in below Table 1.

 

Table 1: Composition of Bicalutamide Tablets 50mg

Sr. No.	Ingredient	Specification	Mg/tablet
			Batch. No.: BCT-003-22 B.Size: 5000 Tablets
Stage- A Dry mixing
1	Bicalutamide	USP	50
2	Anhydrous Lactose (Super Tab 21 AN)	NF/Ph.Eur.	63
3	Maize Starch (C☆PharmGel)	NF/Ph.Eur.	9
4	Sodium Starch Glycolate (Primojel/Type A)	NF/Ph.Eur.	4
Stage- B Blending-I
1	Colloidal Silicone Dioxide (Aerosil 200)	NF/Ph.Eur.	0.3
2	Talc	USP/Ph.Eur.	0.6
Stage - C Lubrication-I
1	Magnesium Stearate	NF/Ph.Eur.	0.6
Stage - D Blending-II
1	Talc	USP	0.5
Stage - E Lubrication-II
1	Magnesium Stearate	NF/Ph.Eur.	0.6
Net weight of Core Tablet (mg)			128

 

Factorial Design was applied to determine design space, formulation critical attributes, and the effect of change in the level of Sodium Starch Glycolate (Primojel/ Type A) and Magnesium Stearate, Pregelatinised starch (Lycatab)/ Anhydrous Lactose/Lactose Anhydrous (Super Tab 21 AN) ratio and the Particle size distribution of Anhydrous lactose within supplier's specification on in-vitro drug dissolution. Two level four factor partial factorial design was adopted.

 

RESULTS:

Aqueous Solubility as Function of pH:

Table 2: Quantitative solubility of Bicalutamide at different pH aqueous system

Solvent Media	Bicalutamide (Batch No: BI-22-48876)
	Quantitative solubility (mg/ml)	Dose Solubility Volume* (Calculated at 37ºC)
		Maximum Dose (50mg)
0.1 N HCL, pH 1.2	29.61	0.84
0.01N HCL, pH 2.1	3.4	7.35
Acetate buffer, pH 2.8	44.73	0.56
Acetate buffer, pH 4.5	0.59	42.73
Phosphate buffer, pH 6.0	0.05	500
Phosphate buffer, pH 6.8	0.03	833.33
Phosphate buffer, pH 7.2	0.03	833.33
Phosphate buffer, pH 7.8	0.03	833.33
Purified Water	0.03	833.33

*Dose Solubility Volume: Dose solubility volume is calculated as the highest dose divided by solubility in mg/ml.

The dose solubility volume for Bicalutamide at pH 1.2-7.8 demonstrated that Bicalutamide is soluble at low pH and solubility decreased significantly between pH 2.8-4.5. The solubility remained relatively constant between pH 6.0-7.8 (Poorly Soluble). The absolute aqueous solubility for the Bicalutamide in water is approximately 0.030 mg/ml. The aqueous solubility of the drug substance (Bicalutamide) seems to be low and can have an impact on the in-vitro dissolution.

 

The observed compressibility index and Hausner ratio were 38.333 and 1.462 respectively. A compressibility index>38 and a Hausner ratio> 1.5 indicates very poor flow characteristics.

 

Drug Substance-Excipient Compatibility Study:

Bicalutamide and combination excipients stored at 3 months, 40℃/75%RH, physical and chemical compatibility results are mentioned below in Table 3.

Table 3: Drug Substance-Excipient compatibility studies results (at 3 months, 40℃/75%RH):

Drug: Excipient	Physical Observation		Related Substance
		Bicalutamide Related compound A isomer A (NMT 0.1%)	Bicalutamide Related compound A isomer B (NMT 0.1%)	Bicalutamide Aminobenzo-nitrile (NMT 0.1%)	Desfluro Bicalutamide (NMT 0.2%)	2-fluro Bicalutamide (NMT 0.2%)	Deoxy Bicalutamide (NMT 0.2%)	Bicalutamide sulfide (NMT 0.1%)	Any unspecified Impurity (NMT 0.1%)	Total Impurities (NMT 0.5%)
Bicalutamide	White free-flowing Powder	BQL	BQL	0.006	0.045	0.096	BQL	0.004	0.001	0.055
Bicalutamide: Anhydrous Lactose (Super Tab 21 AN)	White free-flowing Powder	BQL	BQL	0.005	0.078	0.097	0.031	BQL	0.005	0.105
Bicalutamide: Corn Starch (UnipureFL)	White free-flowing Powder	BQL	BQL	0.007	0.089	0.092	BQL	0.006	0.002	0.109
Bicalutamide: Sodium Starch Glycolate Type A (pH 5.5 -7.5)	White free-flowing Powder	BQL	BQL	0.014	0.065	0.01	BQL	BQL	0.006	0.078
Bicalutamide: Magnesium Stearate	White free-flowing Powder	BQL	BQL	0.009	0.097	0.091	0.025	0.004	0.003	0.101
Bicalutamide: Talc	White free-flowing Powder	BQL	BQL	0.008	0.039	0.016	BQL	BQL	0.003	0.104
Bicalutamide: Colloidal Silicone Dioxide	White free-flowing Powder	BQL	BQL	0.005	0.058	0.015	0.026	0.005	0.005	0.108
Bicalutamide: Pregelatinised Starch	White free-flowing Powder	BQL	BQL	0.005	0.093	0.019	0.021	0.005	0.007	0.105

BQL= Below Quantification Limit

 

The details of the Critical excipient are mentioned in Table 4.

 

Table 4: Selected levels of critical excipients

Critical excipient identified	Low level	High level
Anhydrous Lactose/Lactose Anhydrous (Super Tab 21 AN)	Coarse	Fine
Sodium Starch Glycolate (Primojel/Type A)	2.60%	4.60%
Magnesium Stearate	1.15%	1.65%
Pregelatinised starch (Lycatab)/ Anhydrous Lactose/Lactose Anhydrous(Super Tab 21 AN) Ratio	2.83:97.17	10.83;89.17

 

The critical evaluation parameters and acceptance criteria for compressed core tablets are mentioned in Table 5.

 

 

 

 

 

Table 5: Critical evaluation parameters along with acceptance criteria

Critical Evaluation Parameters	Acceptance criteria
Physical appearance (Sticking, Capping, Lamination, etc.)	Acceptable, Free of any defect
Maximum Individual % Weight (mg) Variation from Target	128.00±5%
Maximum Difference of Hardness (kP) from Target	7.5±1.0
Disintegration Time	NMT 15 minutes
% Friability	NMT 1%
% Drug Dissolve	NLT 80 % (Q) in 30 mins

 

The details of the batches and factors are mentioned in Table 6.

 

Table 6: Summary of dependent and independent variables studies for formula optimization

Experimental Runs
Batch No.	PSD of Lactose Anhydrous	Sodium Starch Glycolate	Magnesium Stearate	Starch/Lactose ratio
BCT-001FO-22 (Batch Size: 1000 tablets)	Coarse	2.6	1.15	2.83:97.17
BCT-002FO-22 (Batch Size: 1000 tablets)	Fine	2.6	1.15	10.83:89.17
BCT-003FO-22 (Batch Size: 1000 tablets)	Coarse	4.6	1.15	10.83:89.17
BCT-004FO-22 (Batch Size: 1000 tablets)	Fine	4.6	1.65	10.83:89.17
BCT-005FO-22 (Batch Size: 1000 tablets)	Coarse	2.6	1.65	10.83:89.17
BCT-006FO-22 (Batch Size: 1000 tablets)	Fine	2.6	1.65	2.83:97.17
BCT-007FO-22 (Batch Size: 1000 tablets)	Coarse	4.6	1.65	2.83:97.17
BCT-008FO-22 (Batch Size: 5000 tablets)	Fine	4.6	1.15	2.83:97.17

 

The abovementioned batches in process results arementioned in Table 7.

 

Table 7: Summary of response studies

Batch No.	Physical Appearance	Maximum Individual % weight Variation from Target (128.00 mg)	Maximum Difference of Hardness (kP) from Target	Disintegration Time (min)	% Friability	% Drug Dissolution	CV (AV Value)
BCT-001FO-22	None	1.8	0.5	2min 45 sec	0.3	98	3.01
BCT-002FO-22	None	1.1	0.6	3 min 15 sec	0.31	99	7.05
BCT-003FO-22	None	1.4	1.4	3 min 20 sec	0.38	101	9.75
BCT-004FO-22	None	1.5	1.2	4 min 15 sec	0.36	100	5.95
BCT-005FO-22	None	2	0.8	3 min 45sec	0.22	102	5.65
BCT-006FO-22	None	2.1	0.6	5 min 45 sec	0.41	99	4.15
BCT-007FO-22	None	3.2	0.8	2min 25 sec	0.25	98	8.45
BCT-008FO-22	None	1.5	0.9	3 min 25 sec	0.33	97	5.95
Acceptance Criteria	Acceptable free of any defect	128.00±5%	7.5±1.0	NMT 15 minutes	NMT 1%	In 30min NLT 80% (Q)	NMT 15

 

Figure 1: Pareto Chart of Formulation Variables on Tablets Content Uniformity and % Dissolution at 30 minutes

 

Table 8: Effects of Formulation Variables

Formulation Variable	Effects
	Content Uniformity (%)	% Dissolution at 30 minutes
Main Effect
Concentration of Sodium Starch Glycolate (Primojel/Type A)	2.776	1
Conc of Magnesium Stearate	-1.876	-0.501
Ratio of Pregelatinised starch (Lycatab)/ Anhydrous Lactose/Lactose Anhydrous (Super Tab 21 AN)	1.467	2.01
PSD of Anhydrous Lactose/Lactose Anhydrous (Super Tab 21 AN)	0.581	-2.501
Concentration of SSG* PSD of Anhydrous Lactose/Lactose Anhydrous (Super Tab 21 AN)	-2.224
Concentration of Lubricant*PSD of Anhydrous Lactose/Lactose Anhydrous (Super Tab 21 AN)		1.501
Standardized Effect	12.72	4.301

Note: Negative or positive information about whether the impact of the variable on response is positive or negative.

 

Figure 2: Main Effect of Formulation process variables on Tables CU and (%) Dissolution at 30 minutes

 

DISCUSSION:

Statistical Analysis of Design of Experiments:

Effect of Variables:

A Pareto chart showing the effect of core tablet formulation process variables on Tablet Content Uniformity (%) and % dissolution at 30 minutes.

 

The details of the Formulation Variable and its effects on Content Uniformity and Dissolution are mentioned in Table 8.

Main Effect:

The main effect plot showing the impact of formulation variables within in studied range on Tablets Content uniformity and % Dissolution at 30 minutes is represented below.

 

The absolute effect of selected variables within the studied range is less than the standardized effect the Tablet Content Uniformity AV Value is less than 10.0 and D% Dissolution at 30 minutes is more than 98.0% at the studied range of variables.

Table 9: Model Evaluation

Response	Terms included in a reduced model	Coefficient	P-Value	Justification for inclusion
Tablet Content Uniformity (AV Value)	Constant	6.616	0.015	The P-value for all the terms is greater than 0.05
	Sodium Starch Glycolate (Primojel/Type A)	1.388	0.077
	Conc of Lubricant	-0.934	0.112
	The ratio of Pregelatinised starch (Lycatab) to Anhydrous Lactose (Super Tab 21 AN)	0.727	0.145
	PSD of Anhydrous Lactose (Super Tab 21 AN)	0.29	0.337
	Conc of Sodium Starch Glycolate (Primojel/ Type A) *Ratio of starch to Anhydrous Lactose (Super Tab 21 AN)	-0.853	0.125
	Conc of Sodium Starch Glycolate (Primojel/ Type A) *PSD of Anhydrous Lactose (Super Tab 21 AN)	-1.105	0.095

 

Table 10: Model Evaluation

Response	Terms included in the reduced model	Coefficient	P-Value	Justification for inclusion
Tablet % Dissolution at 30 minutes	Constant	97.643	0	The P-value for all the terms is greater than 0.05
	Conc of Sodium Starch Glycolate (Primojel/Type A)	0.49	0.2925
	Conc of Lubricant	-1	0.552
	Conc of Sodium Starch Glycolate (Primojel/ Type A) *Ratio of starch to Anhydrous Lactose (Super Tab 21 AN)	0.249	0.105
	PSD of Anhydrous Lactose (Super Tab 21 AN)	-5.4485	0.0718
	Conc of Lubricant *PSD of Anhydrous Lactose (Super Tab 21 AN)	3	0.168

The p-value for all the formulation variables is greater than 0.05 indicating insignificant for tablet % Dissolution at 30 minutes. The % Dissolution at 30 minutes was greater than 97.0% at the studied range of variables observed. The details are mentioned above in Table 10.

 

Hence it can be concluded that there is no significant impact of selected variables within the studied range on Tablet Content Uniformity and % dissolution at 30 minutes.

 

Model Evaluation:

A mathematical model was evaluated based on statistical terminologies as mentioned in the below Table-9.

The p-value for all the formulation variables is greater than 0.05 indicating insignificant for tablet content uniformity. The tablet content uniformity AV Value is less than 10.0 at a studied range of variables observed. Hence, the range selected will not have any impact on a critical quality attribute (CQA) of a drug product.

 

Stability Data of Formulation Optimization Batch:

The details of the Dissolution results at 40°C/75%RH and 25°C/60%RH stability conditions are mentioned below in Table 11.

 

Table 11: Stability Data for Bicalutamide Tablets 50mg

Product Name: Bicalutamide Tablets50 mg		Manufacturing Date: 30/05/22
Batch No.: BCT-008FO-22		Stability initiation date: 05/06/22
Batch Size: 5000 Tablets		Pack: Tablets packed in Alu-Alu Blister packs
Stability Condition	Station (Months)	Dissolution (30 mins)
Initial	0	98%
	1	99%
	2	98%
40°C/75%RH	3	97%
	6	98%
	3	98%
	6	99%
25°C/60%RH	9	97%
	12	98%

Stability Inference:

The stability study result revealed that the Bicalutamide Tablets 50mg were found stable. The finished product dissolution results did not show any significant difference during storage of the product at 40°C/75%RH, and 25°C/60%RH in the blister pack.

 

Conclusion:

The data on the Factorial Design studies revealed that experimental runs within a selected range of all the independent variables did not show any impact on Critical Quality Attributes and other in-process test results. Hence, the selected range can be considered as a design space within which any change will not have any impact on critical quality attributes of drug products.

 

The Bicalutamide Tablets 50mg formulation optimization, computer-assisted regression analysis, and mathematics model can be utilized as a suitable tablet formulation. The dry granulation process selection and proportion of excipientshave been optimized successfully. A design space depicted that the critical material attributes (CMA) were correlated with Critical Quality Attributes (CQA). The Factorial design implications are used to optimize the formulation of Bicalutamide Tablets 50 mg.

 

CONFLICT OF INTEREST:

There is no conflict of interest.

 

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Accepted on 14.05.2024           © RJPT All right reserved

Research J. Pharm. and Tech 2024; 17(10):4796-4802.