The use of Cyclodextrin-SLS-PEG 4000 Complex to Solubilize Three BCS Class II and IV Drug´S through A Factorial Study Design

Soumaya El Baraka¹, Ali Cherif Chefchaouni¹, Ismail Bennani², Aicha Fahry¹,

Abdelkader Laatiris¹, Naoual Cherkaoui¹, Yasser El Alaoui¹, Younes Rahali¹

¹Team of Formulation and Quality Control of Health Products, Laboratory of Pharmaceutics,

Faculty of Medicine and Pharmacy, Mohammed V University of Rabat, Rabat, Morocco.

²Galenic laboratory of Faculty of Medicine and Pharmacy of Fez,

Mohammed Sidi Benabdellah University of Fez.

*Corresponding Author E-mail: soumayaelbaraka23@gmail.com

ABSTRACT:

Objective: Drugs classified as Class II and IV on the Biopharmaceutical Classification System are commonly associated with solubility challenges. This research aims to investigate the impact of cyclodextrin combined with both PEG 4000 and SLS, individually and in combination, on the enhancement of solubility and dissolution rate of three drugs belonging to BCS Class II (celecoxib and Valsartan) and Class IV (Furosemide). Methods: A series of 2³ factorial experiments were conducted to assess drug solubility in eight selected fluids containing Beta Cyclodextrin, Poly Ethylene Glycol 4000, Sodium Lauryl Sulphate, both separately and in binary and ternary combinations. Solid inclusion complexes of each drug with beta Cyclodextrin, PEG 4000 and SLS were prepared using the kneading method. The impact of each excipient on dissolution rates was evaluated through a2³ factorial design. Results: The presence of the studied excipients significantly improved the solubility of the three drugs under investigation. Celecoxib solubility was highly enhanced by Cyclodextrin combined toPEG 4000 and SLS(2,77 ratio). Furosemide solubility was highly enhanced by Cyclodextrin combinedto SLS (ac) (2,96 ratio). And valsartan solubility by beta cyclodextrin combined to PEG 4000 and SLS(2,43 ratio). Among dissolution rates, the addition of PEG 4000 and SLS alongside Cyclodextrin led to even more substantial improvements: 14.96-ratio and 7.34-ratio enhancements, respectively on celecoxib dissolution rates, and 9,22-ratio and 11,73-ratio increases, respectively, for furosemide dissolution rates, then.2,09-ratio and 1,88-ratio, respectively on valsartan dissolution rates. Conclusion: Sodium Lauryl Sulphate demonstrates efficacy as a solubilizer both independently and in conjunction with ßCD and PEG 4000, effectively enhancing the solubility and dissolution rate of the selected BCS Class II and IV drugs.

KEYWORDS: Solubility, Dissolution, Cyclodextrin, SLS, PEG 4000.

INTRODUCTION:

Newly developed drugs formulations are usually associated to poor water solubility which can be a limiting factor for oral drug absorption and dissolution rates. Many approaches can be adopted to enhance solubility rates¹, as reducing particle sizes², salt formation³, the use of solubilization agent as co solvent⁴, surfactant and co surfactant or cyclodextrins (CD)⁵.

Class II «low solubility, low permeability» drugs in Biopharmaceutical Classification are those that presents the most solubility problems⁶.

Cyclodextrins (CD) has good acceptance in drugs formulation in last years as they can enhance hydrophobic Active Pharmaceutical Ingredients (API) solubilities⁷, protect drugs from environmental degradation⁸, and even act as drug delivery vehicles, as they can target specific tissues or cells⁸. CD are cyclic oligosaccharides linked together by alpha-1,4 glycosidic bonds, and composed of six, seven, or eight glucose units⁹. Their cone-shaped structure with a hydrophilic outer surface, and a hydrophobic cavity in the center allows insoluble drug´s encapsulation then solubilization¹⁰. CD can be used alone or combined to one, two or more other solubilizers.

Sodium Lauryl Sulfate (SLS) is an anionic surfactant widely used to increase drugs solubility¹¹, by forming micelles in aqueous solutions, and incorporating it into its hydrophobic core. Furthermore, higher molecular weight as Poly Ethylene Glycol 4000 (PEG 4000)is known to be suitable for increasing drug solubility¹².

Three distinct pharmaceutical agents, namely Valsartan (VST), Furosemide (FSD), and Celecoxib (CCX), have been identified to exhibit challenges in solubility, thereby exerting potential repercussions on their bioavailability and therapeutic efficacy within the human body. VST functions as an angiotensin II receptor antagonist, primarily indicated for the management of hypertension and heart failure¹³. FSD serves as a loop diuretic and is employed in the treatment of conditions such as edema and hypertension¹⁴. Celecoxib, on the other hand, operates as a nonsteroidal anti-inflammatory drug¹⁵, frequently prescribed for the mitigation of pain and inflammatory ailments. The intrinsic poor water solubility of VST, FSD, and CCX imposes constraints on their dissolution kinetics and subsequent absorption within the gastrointestinal milieu. Importantly, these three compounds are classified as class II drugs within the Biopharmaceutical Classification System (BCS) for VST and CCX^7,15, and Class IV for FSD¹⁴, indicative of their characteristic features of low aqueous solubility.

The objective of this study is to assess the impact of the use of cyclodextrin combined with each SLS, PEG 4000 individually, and in binary and ternary combinations, by evaluating the enhancement of solubility and dissolution rate on three BCS class II drugs namely Valsartan (VST), Furosemide (FSD) and celecoxib (CCX) in a serie of 2³factorial study.

MATERIAL AND METHODS:

Material:

VST, FSD and CCX were all gift samples, CCX from Pharmaceutical Institute Industry, Furosemide from Pharma 5, and Valsartan from Sheikh Zaid Foundation Bioequivalence Center.

Cyclodextrin beta was bought from Sigma laboratory, SLS and PEG 4000 were purchased from BASF (Ludwigshafen, Germany) and Merck (Germany), respectively. Ethanol was purchased from VWR BDH Prolabo® (France).

All other materials were distilled water and reagents.

Analytical method:

UV/visible spectrophotometer (Shimadzu UV 2450, Japan) was used for absorbance measurement. Linearity, precision, interference and accuracy were validated for the methods that obeyed Beer Lamber´s law in the concentration range studied. A Standard drug solution was repeated for six times (n=6), coefficient variation and relative error were less than 1% and 0,5%.

Solubility studies:

An excess of each API (50mg) was incorporated into 10 mL of each selected fluid, and was placed within conical capped vessels. The mixtures were then gently agitated for 24hours at room temperature (25±1°C) using a magnetic stirrer. Following the 24-hour agitation period, 2mL of the supernatants were swiftly retrieved and subjected to immediate filtration through Whatman filter paper (0.45µm). The resultant filtrates were diluted in a ratio of 1:10 (0.1mL of filtrate combined with 1 mL of ethanol) and subsequently assessed at 249nm, 256nm and, 215nm respectively for VST, FSD and CCX. Each analysis was replicated five times (n = 5)

Dissolution studies:

To evaluate both the individual and combined effects of each excipient (βCD, SLS, PEG 4000) on the dissolution rates of VST (i), FSD (ii), and CCX (iii), solid inclusion complexes of the drugs with βCD were meticulously prepared in the presence and absence of SLS and PEG 4000, through a 2³factorial design.

The preparation of the CD-API solid inclusion complexes was accomplished through the kneading method¹⁷, employing a 2:1 βCD-API ratio, with variations encompassing the presence or absence of SLS (0% and 2%) and PEG 4000 (0% and 2%). In this process, VST, FSD, and CCX were triturated together with a water-methanol blend in a 1:1 ratio within a mortar, resulting in a dense paste that underwent kneading for 30 minutes before being dried at 55°C until achieving complete dryness. The resultant dried material was further ground into a fine powder using a mortar and subsequently sifted through a No. 120 mesh sieve.

For each experimental trial, quantities equivalent to 40 mg of VST, 60 mg of FSD, and 100 mg of CCX were employed, involving a total of eight distinct samples types within the 2³factorial study. Each mixture types were filled in 5 hard capsules size 0, and theconsidered combinations was:Pure drug (1); API- ßCD (1:2) inclusion binary complex (a); API–PEG 4000 (2%) binary mixture (b); API-ßCD (1:2) – PEG 4000 (2%) ternary complex (ab); API – SLS(2%) binary mixture (c); API -ßCD (1:2) – SLS(2%) ternary complex (ac); API–PEG 4000 (2%) – SLS(2%) ternary complex (bc); API -ßCD (1:2) – PEG 4000 (2%) – SLS(2%) complex (abc).

Dissolution rates were determined using a dissolution test apparatus II (Pharma test) with a basket stirrer at 50 rpm. Each sample comprised API and meticulously prepared API-CD complexes, containing 40mg of VST, 60 mg of FSD, and 100mg of CCX. Dissolution rates were subsequently assessed in distinct dissolution media: 900mL of pH 6.8 phosphate buffer, pH 8.4 alkaline borate buffer, and pH 7.4 phosphate buffer, while maintaining a controlled temperature of 37±1°C. At regular intervals, 10mL equivalents of the dissolution media samples were meticulously filtered through Whatman paper, followed by a subsequent dilution step using a 1:10 ethanol ratio. Analysis was then conducted at wavelengths of 249nm, 256nm, and 215nm respectively, with the used media replaced by fresh fluid after each assessment. The entire dissolution procedure was repeated for five replicates (n=5) for each API.

ANOVA Data Analysis: Subsequently, an analysis of variance (ANOVA) was employed to scrutinize the outcomes of the factorial experiments. This analytical approach allowed for an in-depth exploration of the solubility and dissolution data, serving to elucidate both the individual contributions and the synergistic impacts of the factors under examinationnamely, βCD, PEG 4000, and SLS.

RESULTS AND DISCUSSION:

Two varying levels of βCD (0 and 5mM) (Factor a), as well as two distinct concentrations of PEG 4000 (0 and 2%) (Factor b) and SLS (0 and 2%) (Factor c), were systematically incorporated into each experimental setup. This arrangement facilitated the meticulous evaluation of both the independent and collective influences of these excipients on the aqueous solubility profiles of VST (i), FSD (ii), and CCX (iii) across a comprehensive series of 23-factorial experiments. Corresponding treatments encompassed: purified water (1), water with 5mM βCD (a); water containing 2% PEG 4000 (b); water with 5mM βCD and 2% PEG 4000 (ab); water containing 2% SLS (c); water with 5mM βCD and 2% SLS (ac); water containing 2% PEG 4000 and 2% SLS (bc); and water with 5mM βCD along with 2% of eachPEG 4000 and SLS (abc).

The solubility evaluation, outlined in Tables 1, 2, and 3, illustrates the aqueous solubility of each API within the aforementioned media under scrutiny, with each assessment performed five times (n=5). It is noteworthy that the inclusion of βCD, PEG 4000, and SLS, both individually and in various combinations, distinctly elevated the aqueous solubility of the investigated APIs.

To ascertain the significance of the primary and intertwined effects of βCD, PEG 4000, and SLS on solubility, an analysis of variance (ANOVA) was undertaken. The individual and collective impacts of βCD, PEG 4000, and SLS on VST (i), FSD (ii), and CCX (iii) were determined to be highly significant (P < 0.01).

Solubility results

Table1: Solubility of CCX in Various Fluids as per 2³- Factorial Study

FLUIDS	Solubility (MG/ML) (N=5) (X±SD)	Increase in Solubility (Ratio)	Significance
Distilled water (1)	0,213±0,01
Water containing 5 mM ßCD (a)	0,325±0,04	1,53	P < 0.01
Water containing 2% PEG 4000 (b)	0,387±0,03	1,82	P < 0.01
Water containing 5 mM ßCD and 2% PEG 4000 (ab)	0,402±0,06	1,89	P < 0.01
Water containing 2% SLS ( c)	0,242±0,05	1,14	P < 0.01
Water containing 5 mM ßCD and 2% SLS (ac)	0,523±0,06	2,46	P < 0.01
Water containing 2% PEG 4000and 2% SLS (bc)	0,345±0,03	1,62	P < 0.01
Water containing 5 mM ßCD, 2% PEG 4000 and 2% SLS (abc)	0,589±0,02	2,77	P < 0.01

Table2: Solubility of FSD in Various Fluids as per 2³- Factorial Study

FLUIDS	Solubility (MG/ML) (N=5) (X±SD)	Increase in Solubility (RATIO)	Significance
Distilled water (1)	0,145±0,01
Water containing 5 mM ßCD (a)	0,314±0,04	2,17	P < 0.01
Water containing 2% PEG 4000 (b)	0,213±0,03	1,47	P < 0.01
Water containing 5 mM ßCD and 2% PEG 4000 (ab)	0,376±0,06	2,59	P < 0.01
Water containing 2% SLS ( c)	0,239±0,05	1,65	P < 0.01
Water containing 5 mM ßCD and 2% SLS (ac)	0,429±0,06	2,96	P < 0.01
Water containing 2% PEG 4000and 2% SLS (bc)	0,241±0,03	1,66	P < 0.01
Water containing 5 mM ßCD, 2% PEG 4000 and 2% SLS (abc)	0,419±0,02	2,89	P < 0.01

Table 3: Solubility of VST in Various Fluids as per 2³- Factorial Study

FLUIDS	Solubility (MG/ML) (N=5) (X±SD)	Increase in Solubility (RATIO)	Significance
Distilled water (1)	0,189±0,03
Water containing 5 mM ßCD (a)	0,256±0,04	1,35	P < 0.01
Water containing 2% PEG 4000 (b)	0,305±0,06	1,61	P < 0.01
Water containing 5 mM ßCD and 2% PEG 4000 (ab)	0,458±0,04	1,61	P < 0.01
Water containing 2% SLS ( c)	0,265±0,01	1,4	P < 0.01
Water containing 5 mM ßCD and 2% SLS (ac)	0,408±0,02	2,16	P < 0.01
Water containing 2% PEG 4000and 2% SLS (bc)	0,230±0,04	1,22	P < 0.01
Water containing 5 mM ßCD, 2% PEG 4000 and 2% SLS (abc)	0,460±0,05	2,43	P < 0.01

Table 4: Dissolution rates of CCX– ßCD complex systems prepared as per 2³Factorial Study

Complex	Composition	Dissolution Rates/MIN	Increaseindissolution Rates(RATIO)
F1	CCX	0,92
Fa	CCX-ßCD (1:2)	1,53	1,66
Fb	CCX-PEG 4000 (2%)	3,25	3,53
Fab	CCX-ßCD (1:2) - PEG 4000 (2%)	13,76	14,96
Fc	CCX-SLS (2%)	1,42	1,54
Fac	CCX- ßCD (1:2)-SLS (2%)	6,75	7,34
Fbc	CCX-PEG 4000 (2%)-SLS (2%)	3,93	4,27
Fabc	CCX- ßCD (1:2)-PEG 4000 (2%)-SLS (2%)	5,83	6,34

Table 5: Dissolution rates of FSD – ßCD complex systems prepared as per 2³Factorial Study

Complex	Composition	Dissolution Rates/Min	Increase In Dissolution Rates(Ratio)
F1	FSD	2,13
Fa	FSD-ßCD (1:2)	9,74	4,57
Fb	FSD-PEG 4000 (2%)	7,51	3,53
Fab	FSD-ßCD (1:2) - PEG 4000 (2%)	19,63	9,22
Fc	FSD-SLS (2%)	4,89	2,3
Fac	FSD- ßCD (1:2)-SLS (2%)	24,98	11,73
Fbc	FSD-PEG 4000 (2%)-SLS (2%)	4,57	2,15
Fabc	FSD- ßCD (1:2)-PEG 4000 (2%)-SLS (2%)	28,56	13,41

Table 6: Dissolution rates of VST – ßCD complex systems prepared as per 2³Factorial Study

Complex	Composition	Dissolution Rates/Min	Increase in Dissolution Rates(Ratio)
F1	VST	3,45
Fa	VST-ßCD (1:2)	3,87	1,12
Fb	VST-PEG 4000 (2%)	6,45	1,87
Fab	VST-ßCD (1:2) - PEG 4000 (2%)	7,22	2,09
Fc	VST-SLS (2%)	14,57	4,22
Fac	VST- ßCD (1:2)-SLS (2%)	6,48	1,88
Fbc	VST-PEG 4000 (2%)-SLS (2%)	5,96	1,73
Fabc	VST- ßCD (1:2)-PEG 4000 (2%)-SLS (2%)	6,24	1,81

Dissolution rates:

Within Tables 4, 5, and 6, the ANOVA analysis concerning dissolution rates unveils significant findings: the individual primary effects of βCD, PEG 4000, and SLS, along with their collective impacts in elevating the dissolution rate (K1), were of utmost significance (P < 0.01) for each of the API entities examined.

Table 4 reveals insights into the dissolution rate of CCX: βCD contributed to a 1,66-ratio enhancement in dissolution rate, with the introduction of PEG 4000 and SLS with CD yielding respective increments of 14,96-ratio and 7,34-ratio in CCX's dissolution rate.

Proceeding to Table 5, it is evident that βCD facilitated a 4,57-ratio elevation in FSD's dissolution rate. The incorporation of PEG 4000 and SLSto CD complex resulted in even more pronounced enhancements, marking 9,22-ratio and 11,73-ratio increases, respectively, in the dissolution rate of FSD.

Lastly, Table 6 delves into VST's dissolution rate. Notably, βCD alone, yielded a 1,12-ratio increase in VST's dissolution rate. However, when coupled with PEG 4000 and SLS, this enhancement became even more pronounced, achieving increments of 2,09-ratio and 1,88-ratio, respectively. On the other hand, it is pertinent to highlight that SLS singularly showcased the most substantial improvement, reaching an impressive 4,22-ratio enhancement in dissolution rate.

Globally, the study underscores the efficacy of PEG 4000 as a commendable solubilizer, both autonomously and in synergy with βCD and SLS, for augmenting the solubility and dissolution rate of the selected trio of BCS class II drugs. In light of these findings, the combination of PEG 4000 with βCD and SLS emerges as a promising approach to foster heightened solubility and enhanced dissolution rates for drugs classified within BCS Class II and IV drugs.

CONCLUSION:

The individual contributions of beta CD, PEG 4000, and SLS to the solubility enhancement of VST, FSD, and CCX were distinct and pronounced, both when utilized in isolation and within binary and ternary combinations.The outcomes of ANOVA analysis underscored the substantial significance (P<0.01) of the independent and combined impacts of beta CD, PEG 4000, and SLS on elevating the solubilities of the three drugs.

In light of these findings, PEG 4000 emerged as a particularly fitting solubilizer, both when employed individually and in conjunction with beta CD and SLS, presenting a promising avenue for augmenting both the solubility and dissolution rate of the selected trio of BCS class II drugs.

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Received on 28.08.2023 Modified on 12.11.2023

Research J. Pharm. and Tech. 2024; 17(3):1207-1211.

DOI: 10.52711/0974-360X.2024.00188