INTRODUCTION:

Solid dispersions (SDs) are a type of dispersion having one or extra API in an inert carrier at solid-state. SDs is one of the mightily confident tactics for solubility. The term SDs tells that a set of solid products composed of minimum of two different mixtures, usually a hydrophilic matrix and a lipophilic drug. The matrix may be crystalline or amorphous.¹

These enrich the dissolution of hydrophobic drugs thereby enhancing oral absorption and bioavailability of BCS Class II drugs. It helps to increase the dissolution, absorption and beneficial effectiveness of drugs in dosage forms.² These are also used to increase stability further used to formulate fast discharge grooming dose in a sustained discharge dosage form.

A Factorial design is a testing whose design with 2 or withal factors each with different likely values or levels. It is applied in optimization practices. It depends on independent variables for expansion of new formulation and also based on levels further coding. It may be both full factorial design or fractional factorial design. Factorial design plays important role in Formulation and Processing, High-performance liquid chromatographic analysis, a study of pharmacokinetic constraints and formulation of culture medium in Virological studies.

SDs are developed by different practices such as^3,4,5

· Solvent method

· Melt Extrusion

· Melting method

· Lyophilizing

· Solvent melting

· Melt Agglomeration

· Super Critical Fluid

· Co-precipitation

· Gel-entrapment

· Kneading

Types of SDs

Innumerable varieties of SDs were as follows^6,7

Eutectic mixtures:

A simple eutectic mixture entails two substances that are fusible in the liquid state but only to a very certain range in the solid-state. It is set up by fast cementing of melded soften of two components that show total fluid miscibility however insignificant strong arrangement.

Amorphous precipitation in a crystalline matrix:

It is like that of eutectic blends yet just contrast in medication encouraged as shapeless structure.

Solid solution:

These consist of one phase regardless of the integer of mixtures. In this the particle size has been slashed to its absolute minimum viz. the molecular extents and the dissolution rate (DR) is identified by the DR of the carrier. They are classified based on their miscibility as continuous and discontinuous.

Continuous solid solutions:

In this, the elements are fusible in all extents. Hypothetically, it tells that the bonding strength amid the two components is tenacious than the bonding strength among the molecules of every discrete element.

Discontinuous solid solutions:

In this, the solubility of one of the substances in the other is restricted. It has been advised that the term `solid solution' is applicable only when the communal solubility of the two mixtures exceeds 5%.

The merits and pitfalls of SD were as follows^8,9

Advantages of SDs:

· To reduce particle size

· To improve wettability

· To improve the porosity of drug

· To reduce crystalline structures of a drug into an amorphous form

· To increase solubility in water of hydrophobic drug.

Disadvantages of SDs:

· A major disadvantage is Instability

· On aging these shows decrease in DR

· Due to absorption of crystal growth, moisture, phase parting, there is a conversion of a drug from metastable form to stable form which leads to decreased solubility

Characterization of SDs:

Once SD prepared, they must be assessed for the following constraints^10,11 (Fig.1)

Fig. 1: Various constraints to be employed to assess SD

Trial and error systems are outdated in the present research for selecting the proportions of excipients and their effect on the formulation and its optimization. To resolve all these issues factorial designs came in the present trend.^12,13,14

Factorial Design (FD):

Conventional examination draws near, typically study the effect of each factor in turn, because of its possibility to control genuinely, and just one factor can be concentrated each time. If 2 components are attempted, they will be between dependent, and bogus outcomes will arise. The Design of experiments (DOE) is a fundamental piece of multivariate examination. Notwithstanding, DOE is perceived as a settlement with a halfway numeral of components. The goals of DOE are screening reaction and streamlining. In FD, all possible blends of the degrees of the variables are investigated in every impersonation. In FD the levels are assigned as 'high' (+1) and 'low' (- 1), and all the information factors are called FD in two levels. For a 2-level plan, the elements perhaps 2, 3, 4, 5, 6, 7, and so on. The whole number of runs will be 4, 8, 16, 32, 64, and 128 separately. Over 5 factors the numeral of runs will be expanded, so partial FD or Plackett-Burman plan (PBD) is preferred 3². For 2-4 factors, the screening objective is FD, and the reaction surface objectives are Central composite (CCD) or Box-Behnken plan (BBD). Furthermore, for 5 and withal factors, the screening objective is FD or PBD, and the reaction surface objectives are reasonable screening3³. The commonly utilized programming for FD is Design-expert/STATISTICA/Minitab. These plans were made by entering a controllable free factor to get an attractive yield called the reliant variable.

Merits of FD:

The benefits of FD as summarized as follows

· Extra capable than each factor in turn.

· FD is compulsory when associations might be available to sidestep misleading suppositions.

· The ends are powerful over a diversity of investigational conditions.

· Saves time and account as it has negligible disappointments.

· FD is an expansive procedure to give settling

· FD permits the assets of a factor to be evaluated at a few degrees of the additional components

· FD is an all the withal incredible asset for getting diminished blunders and modification in the test

· FD approach is savvy and done instantly time

De merits of FD:

FD has not many faults as informed below:

· The size of the preliminary will upsurge with the quantities of variables.

· Tough to make surefire the investigational units are reliable if the amounts of medicines are immense.

· Problematic to comprehend the huge size of the factorial test essentially when the interface among factors exists.

· Need an additional time, passive consent, and management of spreading two dealings at the comparable spell.

· Data investigation and random might be an extra exertion.

Factorial plans are acquiring fascination from numerous analysts as they are genuine examination configuration models, which include controlling numerous components (free factors) that can be controlled/fluctuated to look at the fundamental impacts on result boundaries (subordinate factors). Factorial planning helps in distinguishing the associations among the factors by that a result of clear quality can be delivered. Numerous fruitful exertions were made in SD by factorial designs (Table 1).

Table 1: Various successful reports on solid dispersion by factorial design

Name of the drug	Polymer used	Design	Independent variable	Dependent variable
Celecoxib¹⁵	Poly Vinyl Pyrrolidone (PVP) VA64 sodium dodecylsulphate (SDS)	3²full factorial design (FFD)	PVP VA64 concentration (X1), SDS concentration (X₂) and milling times (X₃)	Particle size (PS) (Y1), polydispersity index (PDI) (Y₂) and zeta potential (Y₃)
Atorvastatin calcium¹⁶	Beta cyclodextrin (β-CD) and PVP-K30	3²FFD	Croscarmellose sodium (X₁) and adsorbent Neusilin US2 (X₂)	Disintegration time (DT), friability and Hardness
Repaglinide¹⁷	Poly Ethyl Glycol (PEG) 8000, Pluronic F 127 and Gelucire 44/14	3² central composite design (CCD)	Concentration of PEG 8000, Gelucire 44/14 and Pluronic F127	Cumulative drug release (CDR), Solubility
Meloxicam¹⁸	MLX, Crospovidone (CP) and poloxamer188	2³ FFD	%CP (X1), the mannitol-avicel ratio (X2), and the compression force (X3)	The hardness, DT and the % meloxicam dissolved after 30 min.
Nisoldipine¹⁹	PVP K30 and poloxamer 188	3² FFD	Polymer concentration	Solubility and tensile strength of amorphous SD compact
Candesartan²⁰	CP	3²FFD	Camphor (X₁), and CP (X₂),	DT (Y₁), %friability (Y₂) and wetting time (Y₃)
Etodolac²¹	Ethyl cellulose (EC), Eudragit S 100 and PVP K 30	3² FFD	Polymers concentration	CDR and Solubility
Cefuroxime Axetil²²	PVP K30 Soluplus	3² CCD	X₁ and X₂	Drug dissolution (DD) after 2 h (D₂) and Permeability after 4 hours (P₄)
Felodipine²³	Eudragit L 100, hydroxypropyl methyl cellulose (HPMC) K4M	3² FFD	Polymers concentration	release rate constant (R1)
Carbamazepine²⁴	Ethocel standard 45 premium and Eudragit RL 100	2²FFD	Polymers concentration	DR
Metformin HCl²⁵	HPMC K-100, EC, Eudragit RL PO, RS PO and Compritol 888 ATO)	2² FFD	effect of polymer type (X₁) and drug: polymer ratio(X₂)	DR at 1h (Y₁), DR at 3h (Y₂), DR at 10h (Y₃), Angle of Repose (AR) (Y₄) and Hausner ratio (Y₅)
Rivaroxaban²⁶	Gelucire 48/16	3²BBD	Polymers concentration	PS (Y1) DD (Y2)
Nisoldipine²⁷	Copovidone and Poloxamer	2³ FFD	Polymers concentration	DD and time to dissolve 90% drug (T₉₀)
Labrasol and Transuctol²⁸	Poloxamer 188.	2³ FFD	Polymers concentration	DR
Ibuprofen²⁹	PEG 4000 and Starcap 1500	3³ BBD	Polymers concentration	% DR after 10 min (Q₁₀) and AR
Lamotrigine³⁰	β-cyclodextrin and PVP-K30	3²FFD	Polymers concentration	DT, % friability and wetting time
Nimesulide³¹	Starch 1500 and Poloxamer 188	2² FFD	Polymers concentration	Dissolution rate (DR) (k₁) and dissolution efficacy (DE₃₀)
Valdecoxib³²	Starch 1500 Poloxamer 188	2² FFD	Polymers concentration	DR and DE₃₀
Carvedilol³³	polyvinyl caprolactam–polyvinyl acetate–PEG	3² FFD	Polymers concentration	The saturated solubility (Y₁)
Olanzapine³⁴	PEG	D-optimal response surface design	Polymer concentration (X₁) and drug concentration(X₂)	DR
Aceclofenac³⁵	Starch phosphate and a water-soluble surfactant namely Gelucire 50/13	2² FFD	Polymer concentration	DR and DE₃₀
Telmisartan³⁶	Poloxamer 407, PEG 6000	2 ² FFD	Polymer concentration	DR and Solubility
Glipezide³⁷	PEG 4000 and PEG 6000	2 ² CCD	Polymer concentration	Solubility (%) and CDR
Meloxicam³⁸	PVP and PEG6000	3 ²FFD	Polymer concentration	Drug content (DC), In vivo and in vitro drug release
Glimepiride³⁹	PEG 6000 and PVP K25	2³FFD	Polymer concentration (X₁) and drug concentration(X₂)	in vitro DD after 30 min
Aceclofenac⁴⁰	PVP and PEG-6000	3² FFD	Polymer concentration (X₁) and drug concentration(X₂)	DC and in vitro DD
Flavones of Hippophae rhamnoides L.⁴¹	Poloxamer- 188	3²FFD	amount of solvent (X₁) and the drug-polymer ratio (X₂)	% of drug dissolved in 10 min (Q10)
Valsartan⁴²	gelucire-50/13 and aeroperl-300pharma	3² FFD	gelucire-50/13 and aeroperl-300pharma®	DD and flow properties
Nimesulide⁴³	D-mannitol and PEG 4000	3² FFD	the effects of the drug/carrier ratio (X₁, 10 and 20%) and the method of preparation (X₂, physical or co-melted mixture)	% DR after 60 min (Y₁).
Diclofenac sodium⁴⁴	Eudragit RS 100, Eudragit RL 100	3 ² FFD	Polymers concentration	% drug incorporation (Y₁) and DR at the end of 12 h (Y₂). drug released at the end of 3 h (Y₃)
Carbamazepine⁴⁵	sodium carboxymethyl cellulose, sodium starch glycolate, pregelatinized starch (PGS), and HPMC	3² FFD	Polymers concentration	% drug dissolved and PS

CONCLUSION:

Solid dispersions play an important role in increasing the solubility of poor water-soluble drugs. They upsurge the solubility by growing the dissolution rate of the drugs. Thus, these are widely imploding in formulating Lipophilic drugs and thus increase their Bioavailability. These are set by various approaches and among those means mostly are set by Melt extrusion means by using polymers HPMC, PEG and PVP were mostly employed. At last, the authors conclude that solid dispersions are one of the major approaches in increasing the Bioavailability of the drug and factorial design in optimizing the proportions of polymers/ingredient and their effect on final outcome of the formulation that helps in making the right formulation with minimal utilization of ingredients in a short time. Nowadays new approaches have been engaged in formulating solid dispersions to augment the bioavailability of the drugs through good drug release profiles.

FINANCIAL SUPPORT AND SPONSORSHIP:

Nil

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

ACKNOWLEDGEMENT:

The authors are thankful to the college management for providing the facilities and encouragement for doing this work.

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Received on 05.04.2021 Modified on 25.04.2021

Asian Journal of Research in Chemistry. 2021; 14(4):297-301.

DOI: 10.52711/0974-4150.2021.00051