Review on Optimization base Emulgel Formulation
Mayuresh. R. Redkar*, Priyajit S Hasabe, Suraj. T. Jadhav, Pankaj S Mane, Deepak J Kare
Department of Pharmaceutics. Shree Santkrupa Collage of Pharmacy, Ghogaon
*Corresponding Author E-mail: mayuresh.redkar@gmail.com
ABSTRACT:
The aim of the present research work is to decrease the systemic side effects and to create a more pronounced effect of emulgel of tretinoin with lower doses of the drug. Emulgel emerged as one of the most interesting topical drug delivery system as it has dual release control system. Also the stability of emulsion is increased when it is incorporated into gel. The emulgel was developed using polymers like carbopol 940 (1:1) of gel and emulsion. Drug-excipients interaction was characterized by FTIR studies. The topical emulgel was prepared by preparing emulsion and gel separately and incorporation emulsion into the gel. The emulgel was evaluated for their physical appearance, pH evaluation, Spreadability, rheological study, drug content, in vitro permeation study and stability study. After all evaluation it can be concluded that tretinoin emulgel could increase the drug permeability across the membrane and fast release of the drug could be achieved successfully. Objective and aim- The aim of present study was to develop an emulgel formulation of Tretinoin gel using Carbopol 940 or HPMC as a gelling agent. The influence of the type of gelling agent and the concentration of both the oil phase and emulsifying agent on the release of the drug and its microbial activity were investigate using 23 factorial design in addition, rheological properties were also evaluated. Conclusion- The present work is to develop tretinoin emulgel adaptable topical drug delivery systems which provide protection against oxidation, fast absorption, and prolonged release and enables reduction in dose and evaluate the emulgel using an ideal topical drug candidate of Tretinoin by suitable method with its release. Tretinoin is widely used in topical acne treatment at 0.025% and 0.05% concentrations. Tretinoin is very effective in 0.05% strength but it cause skin erythema on the applied area.
KEYWORDS: Tretinoin, Emulgel, Gelling agents, Topical drug delivery.
1. INTRODUCTION:
Topical drug delivery can be defined as the application of a drug containing formulation to the skin to directly treat cutaneous disorder. The topical drug delivery includes the use of topical agents like ointments, creams and lotions, but they are usually very sticky causing uneasiness to the patient on application. Moreover they also have less spreading coefficient and need to be applied with rubbing.
They also exhibit the problem of stability. In order to defeat these problems, the use of transparent gels has increased both in cosmetics and in pharmaceutical preparations[1,2].A gel is colloid that is typically 99% by weight liquid, which is immobilized by surface tension between it and a macromolecular network of gelatin fibers. Gels are created by entrapment of large amounts of aqueous or hydro alcoholic liquid in a network of colloidal solid particles. Gel formulations are mainly providing faster drug release as compared to ointments and creams. In spite of many advantages of gels a major limitation is their inability to deliver hydrophobic drugs. To overcome this restriction an emulsion based approach is being used so that a hydrophobic therapeutic moiety can be successfully integrated and delivered through gels. When gels and emulsions are used in combined form the dosage forms are referred as emulgels. Emulsions possess a certain degree of classiness and are easily washed off from skin. They also have a high ability to penetrate the skin. Emulgels for dermatological use have numerous favorable properties such as being thixotropic, greaseless, easily spreadable, easily removable, emollient, non-staining, water soluble, longer shelf life, bio-friendly, transparent and pleasing appearance[2,3].
Emulgel [1-3]:
As the name suggest, they are the combination of gel and emulsion. Both oil-in water (o/w) and water-in-oil (w/o) type of emulsion used as a vehicle to deliver different drugs to the skin. They also have a high ability to penetrate the skin. The presence of the gelling agent in water phase converts a classical emulsion into an emulgel. Molecules can basically penetrate into the skin by three routes: through intact stratum corneum, sweat ducts and sebaceous follicle. The surface of the stratum corneum presents more than 99% of the total skin surface available for percutaneous drug absorption. Passage through this outmost layer is the rate limiting step for percutaneous absorption. The major steps involved in percutaneous absorption include the establishment of a concentration gradient, which provides the driving force for drug movement across the skin, release of drug from the vehicle (partition coefficient), and drug diffusion across the layers of the skin (diffusion coefficient).
Topical treatment is usefull topical skin infection, that is, those confined to the stratum corneum, squamous mucosa etc. such disease include acne, candidiasis, tinea nigra, and fungal keratitis. The most commonly used anti acne drugs for local action are benzoyl peroxide, clindamycin, clarithromycin, Tretinoin and iso Tretinoin.
Advantages [4,5]
1 Avoidance of first pass metabolism.
2 Incorporation of hydrophobic drugs
3 Improve patient compliance.
4 Production feasibility and low preparation cost
5 Convenient and easy to apply.
6 More selective to a specific site
7 Better loading capacity
8 Better stability
9 Short biological half-life and narrow therapeutic window
Disadvantages
1. Skin irritation on contact dermatitis.
2. The possibility of allergenic reactions.
3. The poor permeability of some drug through the skin.
4. Drug of large particle size not easy to absorb through the skin.
5. The occurrence of the bubble during formation of emulgel.
Skin:
Skin is the biggest organ in the body and it is considered as an external defense system. It covers the outside of the body a has other functions beside the defense mechanism it serve as a mechanical barrier between the inner part of the body and the external world
Physiology of Skin and Penetration of Topical Medications:
The skin of an average adult body covers a surface area approximately 2m2 and receives about one third of the blood circulating through the body. An average of every square centimeters of the human skin surface is known to contain, on the average 40-70 hair follicles and 200-300 sweat ducts. Skin surface is slightly acidic and the pH of the skin varies from (4 to 5.6). A sweat and fatty acid secretion influences the pH of the skin surface(7). The skin can be considered to have three distinct layers of tissue that is epidermis, dermis and subcutaneous connective tissue as shown in figure.1.2
Fig 1.1: Structure of skin.
Physiology of skin [8,9]
Figure 1.2: Physiology of Skin
Most of the topical preparations are meant to be applied to the skin. So a basic data of the skin and its physiology function are very important for design to topical dosage form. The skin of an average adult body covers a surface area approximately 2m2 and receives about one-third of the blood circulating through the body. An average human skin surface is known to contain, on the average 40-70 hair follicles and 200-300 sweat ducts on every square centimetre of the skin. The pH of the skin varies from 4 to 5.6. Sweat and fatty acid secreted from sebum influence the pH of the skin surface. The skin can be considered to have four distinct layers of tissue.
Non-viable epidermis:
Stratum corneum is the outermost layer of skin, which is the actual physical barrier to the most substance that comes in contact with the skin. The stratum corneum is 10 to 20 cell layer thick over most of the body. Each cell is a flat, plate-like structure- 34-44 μm long, 25-36 μm wide, 0.5 to 0.20 μm thick with a surface area of 750 to 1200 μm stocked up to each other in brick-like fashion. Stratum corneum consists of lipid (5-15%) including phospholipids, glycosphingolipid, cholesterol sulphate and a neutral lipid, protein (75-85%) which is mainly keratin.
Viable epidermis:
These layers of the skin reside between the stratum corneum and the dermis and have a thickness ranging from 50-100 μm. The structures of the cells in the viable epidermis are physicochemically similar to other living tissues. Cells are held together by tonofibrils. The density of this region is not much different than water. The water content is about 90%.
Dermis:
Just beneath the viable epidermis is the dermis. It is a structural fibrin and very few cells are like it can be found histological in normal tissue. Dermis thickness ranges from 2000 to 3000 μm and consists of a matrix of loose connective tissue composed of fibrous protein embedded in an amphorphose ground substance.
Subcutaneous connective tissue:
The subcutaneous tissue or hypodermis is not actually considered a true part of the structured connective tissue which is composed of loose textured, white, fibrous connective tissue containing blood and lymph vessels, secretary pores of the sweat gland and cutaneous nerves. Most investigators consider drug is permeating through the skin enter the circulatory system before reaching the hypodermis, although the fatty tissue could serve as a depot of the drug.
Advantages and Disadvantages of Topical Drug Delivery System:
Topical drug delivery system have many advantages like local treatment and direct effectiveness of medications like antifungal, anti-bacterial, antiwrinkle, acne preparation and other medications that used for unusual purposes(13). It is characterized by avoidance of gastrointestinal incompatibility and avoidance of first pass metabolism. Also, more selective to a specific site, improve patient compliance and suitability for self-medication. Moreover, we have ability to easily terminate medication when needed however, local drug administration has some disadvantages like skin irritation or possibility of allergenic reactions. Other disadvantage is low penetration of drugs of large particle size, which means not easily to be absorbed through the skin(10,11)
Factors Affecting Topical Absorption of Medications:
A. Physiological Factors of Skin (16)
· Skin thickness
· Lipid content and part of skin.
· Density of sweat glands.
· Skin pH.
· Blood flow.
· Hydration of skin.
· Disease state and inflammation of skin B. Physiochemical Factors of Drug
· Distribution coefficient.
· Molecular weight (<400 Dalton).
· Degree of ionization (unionized drugs gets absorbed well).
· Effect of excipients
Rationale of Emulgel as a Topical Drug Delivery System:
When gel and emulsion are used in combination form, the dosage form is referred to as “emulgel”. Emulgel have major advantages on novel vesicular systems as well as on conventional systems in various aspects: Being thixotropic, greaseless, easily spreadable, easily removable, emollient, non-staining, water-soluble, longer shelf life, bio-friendly, transparent & pleasing appearance. Emulgel dosage form is used for steroids, some antibiotics and it was extended to analgesics and antifungal drugs. Topical agents such as ointment, cream, lotion have many disadvantages.
They are sticky and causing uneasiness to the patients, also have lesser spreading coefficient, and need to be applied sometimes with rubbing. They exhibit the problem of stability also. Due to all these factors within the major group of semisolid preparations, the use of transparent gel has expanded both in cosmetics and in pharmaceutical preparation. However, despite of offering several benefits, gels a colloid system shows major limitations like delivery of hydrophobic drugs. In order to overcome this problem an emulsion-based approach is being used so that even hydrophobic therapeutic moiety can be successfully incorporated and delivered through gel mixtures Emulgel structure was showed in figure 1.3
Fig 1.3: structure of emulgel
Method of preparation of Emulgel:
The method-involved preparation of an o/w emulsion after incorporation of the drug into either oil or aqueous phase depending on the solubility, formation of gel base then mixing the emulsion with the gel base at ratio of 1:1. (18). These steps are showed in figure1.4
METHOD OF PREPARATION(15.16):
STEP1: preparation of gel using gelling agent and water by constant stirring
STEP2: preparation of emulsion. Either o/w or w/o
STEP3: incorporation of emulsion into emulgel
Fig 1.4: Flow chart of method of preparation emulgel
Important Constituents of Emulgel Dosage form
1. Aqueous Material:
This forms the aqueous phase of the emulsion, commonly used agents are water and alcohols. (19)
2. Oils:
Mineral oils, either alone or combined with soft or hard paraffin’s, are widely used both as the vehicle for the drug and for their occlusive and sensory characteristics.
Widely used oils are castor oil, fish liver oils or various fixed oils of vegetable origin (e.g., a rachis, cotton seed, and maize oils(21).
Table 1.1: Use of oils
|
Chemical |
Quantity |
Dosage Form |
|
Light Liquid Paraffine |
7.5% |
Emulsion and Emulgel |
|
Isopropylmyristate |
7-7.5% |
Emulsion |
|
Isopropyl stearate |
7-7.5% |
Emulsion |
|
Propylene glycol |
3-5% |
Gel |
|
3. Emulsifiers: |
|
|
Emulsifying agents are used both to promote emulsification at the time of manufacture and to control stability during a shelf life that can vary from days for extemporaneously prepared emulsions to months or years for commercial preparations. e.g. polyethylene glycol 40 stearate, sorbitan monooleate (span 80), polyoxyethylene sorbitan monooleate (tween 80), stearic acid, sodium stearate(20)[22]
4. Gelling Agents:
These are the agents used to increase the consistency of any dosage form can also be used as thickening agent. [23]
TABLE 1.2 Use of gelling agent
|
Gelling agent |
Quantity: |
Dosage form |
|
Carbopol-934 |
0.5%-2% |
Emulgel |
|
Carbopol-940 |
0.5%-2% |
Emulgel |
|
HPMC-2910 |
2.5% |
Emulgel |
|
HPMC |
3.5% |
Gel |
5. Carbopol:
Carbopol polymers are acrylic acid cross-linked with poly alkenyl ethers or divinyl glycol. It also known as carbomers. Carbomers polymers are cross-linked together and form a micro gel structure that makes them optimal to be used as a drug vehicle for dermatological purposes. They can be used in cases when drug delivery in a controlled manner is desired. These polymers are anionic polymers that need naturalization to become jellified. Organic amines like triethanol amine can be used to naturalize these polymers in liquids. (24)
Carbopol has high viscosity at low concentrations, wide concentration interval and characteristic flow behavior. Also it is characterized by wonderful compatibility with many active ingredients also; it has a good bio adhesive properties and good thermal stability Carbopol is available in several modified structures like carbopol 910, carbopol 934, carbopol 940, etc.[25] They differ in their chemical substitution and their physicochemical properties. Figure.Shows the basic chemical structure of carbopol.
Fig 1.5: Basic structure of Carbapol
6. Permeation Enhancers:
These agents interact with skin constituents to induce a temporary and reversible increase in skin permeability. (26) Like propylene glycol. Penetration enhancers may act by one or more of the following three main mechanisms:
Disruption of the highly ordered structure of stratum corneum lipid.
Interaction with intercellular protein.
Improved partition of the drug, co enhancer or solvent into the stratum corneum.
Mechanism of penetration enhancers:
Penetration enhancers may act by one or more of three main mechanisms:
Disruption of the highly ordered structure of stratum corneum lipid.
1. Interaction with intercellular protein.
2. Improved partition of the drug, co-enhancer or solvent into the stratum corneum.
Formulation aspects of topical preparation:
The present studies are aimed to formulate and characterized an emulgel of selected anti acne, anti wrinkle and antifungal drug for rapid onset of action in the treatment of acne vulgaries or skin disorder and also to improve the bioavability of the drug.
Advantages of Topical Emulgel Formulation are enlisted below:
1. The emulgel formulation must have low allergic potential, good physiological compatibility and high biocompatibility.
2. Facilitate of hydrophobic drugs
3. Better loading capacity
4. Better stability
5. It improved patient compliance
6. Avoidance of first pass metabolism
Topical tretinoin for acne is an over the counter product sold by the Avita or ‘Retin A’. Inspite of being an efficacious drug, it suffers from many drawbacks including skin irritation on contact dermatitis may occur due to the drug and/ or excipients, Poor permeability, Possibility of allergenic reactions, Drugs are larger particle size not easy to absorb through skin, they are sticky causing uneasiness to the patient. It is hypothesized that these disadvantages can be overcome by formulating the drug as an Emulgel owing to its faster drug release. Emulgel has several favourable properties when used for dermal application such as thixotropic, easy spreadable, easy removable, longer shelf life, patient compliance etc. Emulgel formulation applied to the Qbd bases first outlined designing and development process performance.[28 29]
Topical Tretinoin it is available in a number of formulations and concentrations, including 0.025%, 0.05%and 0.1% cream. O.1% and 0.25% gel. Tretinoin works by both comedolysis and by normalizing the maturation of follicular epithelium so that comedo formation ceases.
The present study aims to to preparing an emulgel formulation of Tretinoin using emulsifier and various gelling agent along with the use of permeation enhancer. Tween 20, span 20, were used as emulsifier (2-4%) and gelling agent carbapol 940. The oily phase used comprised on liquid paraffine and cetyl alcohol (5-7.5%). Permeation enhancer include DMSO (5%) menthol (5%), clove oil (8%), oleic acid (1%) which were used so as to enhance the drug release profile of drug.
EXCIPIENTS:
1. Emulsifying Agents:
Emulsifying agents known as emulsifiers are usually used in the formulation of emulsions to stabilize the emulsion by reducing the interfacial tension. Most emulsifying agents are surface-active agents (surfactants). The use of surfactants in emulsions reduces the interfacial tension of the two immiscible liquids by decreasing the repellent force between the liquids and diminishing each liquid’s attraction for its own molecules, according to the surface tension theory of emulsification. Qualities and characteristics of an ideal emulsifying agent include the following:
1. Surface-active and reduces surface tension to below 10 dynes/cm;
2. Adsorbs quickly around the dispersed drops as a condensed, non- adherent film which prevents coalescen
3. Increases the viscosity of the emulsion
4. Odorless, tasteless, or colorless, non-toxic, and nonirritant; Compatible with other excipients and must not interfere with the stability or efficacy of the therapeutic agent.
2. Surfactant:
The second category of emulsifying agents that are commonly used to formulate emulsion is synthetic surfactants. Rees et al. classified synthetic surfactants based on their ionic characteristics as anionic, cationic, non-ionic.
1. Anionic Surfactants:
In the anionic surfactant subgroup, the surfactant ion bears a negative charge in aqueous solutions. The negatively charged anions are responsible for their emulsifying ability. They are widely used in external preparations as O/W emulsifying agents. They are only effective when they are in their ionized form and at a more alkaline pH. The anionic surfactants that are available in the pharmaceutical industry include alkali metal and ammonium soaps, soaps of divalent and trivalent metals, amine soaps, and alkyl sulphates. Ammonium oleate is a good example of an alkali metal and an ammoniumsoap. Triethanolamine is the most widely used amine soap, which is in another class of soaps. They form more stable emulsions than the alkali soap emulsifying agents due to the cation of the amine soap is more balanced and less hydrophilic.
2. Cationic surfactant:
Cationic surfactants play an important role as antiseptic agents, fungicides, germicides, fabric softeners and hair conditioners and also have additional bulk chemical applications. Unlike anionic surfactants, cationic surfactants carry a positive charge. Due to their bactericidal activity, they are widely used in wound cleaning. Treatment and sometimes in fabric rinse softeners. Salts of amines are frequently used in hair care applications due to their conditioning and antistatic properties. Quaternary ammonium compounds (often referred to as ‘quats’) and pyridinium cationic surfactants are extensively used in cosmetics formulations. The reason for their use is cationic emulsifying agents are effective at pH 4-6 which includes the normal pH of the skin, and thus they play a significant role in topical formulations.
3. Nonionic Surfactants:
Nonionic surfactants have a significantly they vary from anionic or cationic surfactants since nonionics have a greater degree of compatibility with other materials. However, they tend to be more expensive. The most commonly used nonionic surfactants include the glyceryl esters, polyoxyethylene glycol esters and ethers, and the sorbitan fatty acid esters and their polyoxyethylene derivatives. Polysorbates are another class of nonionic surfactant, which are polyethylene glycol derivatives of the sorbitan esters. They are used in conjunction with the corresponding sorbitan ester to form a complex condensed film at the oil/water interface.
4. Permeation Enhancers:
These agents interact with skin constituents to induce a temporary and reversible increase in skin permeability. Like propylene glycol. Penetration enhancers may act by one or more of the main mechanisms: Disruption of the highly ordered structure of stratum corneum lipid. Interaction with intercellular protein. Improved partition of the drug, co enhancer or solvent into the stratum corneum.
5. Preservative:
Preservative is important role reduce to microbial growth or decrease the microbial species of formulation. E.g methyl and propyl paraben. Paraben are a class of widely used preservatives in cosmetics and pharmaceutical products. Chemically, they are serious of parahydroxybenzoate acid. Parabens are effective preservatives in many types of formulas. These compounds, and are their salts, are used primarily for their bacterial and fungicidal properties. They are found in shampoos, shaving gels, toothpaste and other topical preparation.
6. Co-solvent:
The solvent, which makes up approximately 90% of the total mass of a reaction solution, plays important role for a solution based chemical reaction. Solubility, equibrium position and reaction rate are all affected by solvent. The mixed solvent system has been used for many used, for e.g. using solvent selection by computer programs, one can now easily predict how to dissolve a given polymer in a mixture of two solvents, neither of which can dissolve the polymer by itself. Though mixed solvent have been used in synthetic chemistry e.g. (DMSO) another role of disinfectant agent added in solvent. The production of stable emulsion requires relatively high concentrations (generally more than 30% w/w) of surfactants. Organic solvents such as, ethanol, propylene glycol (PG), and polyethylene glycol (PEG) are suitable for oral delivery, and they enable the dissolution of large quantities of either the hydrophilic surfactant or the drug in the lipid base.
Two types of solvent
1. Protic solvent e.g. water and methanol
2. Aprotic solvent e.g. DMSO
Gelling agent or thickening agent:
Thickeners may also improve the suspension of other ingredient or emulsion which increase stability of the product. These are one of the thickening authorities used to manufacture the consistency of the formulation. Gelling administrators encounter an abnormal state cross interfacing or alliance when hydrated and scattered in the disseminating medium, or when separated in the scrambling medium. This cross interfacing or relationship of the scattered stage will change the thickness of the scrambling medium. The improvement of the diffusing medium is constrained by the scattered stage, and the consistency is extended. carbapol 940 is effective in thick formulation, very great clarity in water hydroalcoholic topical gels.
QBD: [30]
Quality by Design (QbD) is increasingly becoming an important and widely used technique in the pharmaceutical industry. QbD can be considered to be systems-based approach to design, development, and delivery of any product or service to a consumer. QbD is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes on product and process understanding and process control. It means designing and developing formulations and manufacturing processes to ensure predefined product quality objectives. QbD identifies characteristics that are critical to quality from the perspective of patients, translates them into the attributes that the drug product should possess and establishes how the critical process parameters can be varied to consistently produce a drug product with the desired characteristics. The main concept of QbD is that all final product-critical quality attributes are affected by raw materials and process parameters. Hence, if we identify the cause and effect relationship between the various inputs and responses by carefully designed experiments, we can control the quality of the product by simply controlling the inputs like raw material specifications or process parameters etc. As a result, the final product will always conform to the quality specifications.
In pharmaceutical industry the quality by testing (QbT) system is used to ensure the drug product quality which is an unbending process with itbound specifications for manufactured batches. Flexibility is limited as change at every stage requires submission of a supplement with respect to change to the USFDA (United States Food and Drug Administration). Not like QbT, the quality by design (QbD) concept is an advanced approach to ensure the pharmaceutical- products quality. QbD can recognize the critical material attributes (CMAs) and the critical process parameters (CPPs) concerned in product development through extensive scientific understanding of process. The application of QbD approach to topical dosage forms is in the preliminary stages. For a generic topical product, establishing the mandatory pharmaceutical equivalence and therapeutic equivalence with same components in same concentration with same arrangement is an awkward process. As per the ICH guidelines Q8, pharmaceutical QbD is a systematic approach based on sound science and quality risk management that begins with predefined objectives and emphasizes product and process understanding. However, a lot attention is currently focused on the oral dosage forms, it is equally important for the development of generic topical products as well. Agreed that developing a generic topical product is a complicated and lengthy process, employing QbD possibly will ease the course of development. QbD is first and foremost intended to lessen product variation, improve the process efficiency, and cut costs at various stages. QbD improves the speediness of the product launching onto the market. The FDA guidance, for instance pharmaceutical development (ICH Q8), quality risk assessment (ICH Q9), and pharmaceutical qual-ity systems (ICH Q10) draw attention to the approaches to achieving quality product through QbD. QbD provides identification of CMAs and CPPs which ultimately helps to obtain the product with predefined quality.
Elements of Quality by Design:
Various elements of quality by design as described in ICH Q8 (R2) include Target product profile, Identification of quality attributes, Risk assessment to identify process/product risk, Design space development and Control strategies.
Identifying a Quality Target Product Profile (QTPP):
The quality target product profile (QTPP) is a summary of the quality characteristics or attributes of a drug product that ideally will be achieved and thereby ensure the safety and efficacy of a drug product. The QTPP forms the basis of design for the development of the product. It is both prospective, that is, it describes goals for the development team, and dynamic, that is, the QTPP may be updated or revised at various stages of development as new information is obtained during the development process.
Identification of Critical Quality Attributes (CQA):
Pharmaceutical development consists of product and process design and development. The TPP provides the basis for the ideal dosage form. A critical quality attribute is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. CQAs are generally associated with raw materials (drug substance, excipients), intermediates (in-process materials), and drug product. Drug product CQAs are the properties that are important for product performance, that is, the desired quality, safety, and efficacy.
Quality Attributes Important to the Performance of the Drug Product:
From a clinical perspective, safety and efficacy (product performance) is of prime importance. For example for an oral CR product, it is important to consider attributes that are potentially critical for performance. These may be drug dissolution/release, potency, polymer concentration, polymer viscosity, etc., or any other attribute that can either be substituted for drug release or clinical performance.
Quality Risk Assessment:
A key objective of risk assessment in pharmaceutical development is to identify which material Attributes and process parameters affect the drug product CQAs, that is, to understand and predict sources of variability in the manufacturing process so that an appropriate control strategy can be implemented to ensure that the CQAs are within the desired requirements.
Critical Process Parameters:
A critical process parameter (CPP) is any measurable input (input material attribute or operating parameter) or output (process state variable or output material attribute) of a process step that must be controlled to achieve the desired product quality and process consistency.
Design of Experiment (DOE):[31 32 33]
Response surface methodology (RSM) is a widely practiced approach in the development and optimization of drug delivery devices. Based on the principle of design of experiments (DOE), the methodology encompasses the use of various types of experimental designs, generation of polynomial equations and mapping of the response over the experimental domain to determine the optimum formulation(s). The technique requires minimum experimentation and time, thus proving to be far more effective and cost-effective than the conventional methods of formulating dosage forms. Various RSM computations for the current optimization study were performed employing Design Expert software. Polynomial models including interaction and quadratic terms were generated for all the response variables using multiple linear regression analysis (MLRA) approach. The general form of the MLRA model is represented as Equation below Y=β0 + β1Χ1 + β2Χ2+β3Χ1Χ2+β4Χ12+β5Χ22 where, β0 is the intercept representing the arithmetic average of all quantitative outcomes of 9 runs; β1 to β5 are the coefficients computed from the observed experimental values of Y; X1 and X2 are the coded levels of the independent variable(s). The terms X1X2 represents the interaction. The polynomial equations can be used to draw conclusions after considering the magnitude of coefficient and the mathematical sign it carries (i.e., positive or negative). The analysis of variance (ANOVA) is performed to identify the insignificant factors and reduce the equation in order to get better fit and the best formulation possible.
The choice of an experimental design is an important part of DOE process. The choice depends on a number of aspects including the nature of problem and the study (e.g. the factors and interactions to be studied (e.g. four, six or nine factors, main effects or two way interactions). Numerous statistical experimental designs are known and some of the commonly used designs are:
Null factorial design
1. Central composite design
2. Fractional factorial design
3. Box Behnken design
4. Box Behnken design
5. Placket Burman design
6. Robust design
In the development of pharmaceutical dosage form with appropriate characteristics an important issue is to design an optimized pharmaceutical formulation in a short period of time with minimum trials. For that now a day’s response surface methodology (RSM) is gaining attention to identify and quantify the effect of different formulation variables on the important characteristics. The aim of study was to formulate, optimize and characterize the topical emulgel by statistically designed using 22factorial designs in which two variables the concentration of carbapol and propylene glycol were at different levels. The main interactive influences were tested using statistical model. The response surface plots were generated by software for analysing effect of the independent variables on the response. The effect of formulation variables on the product characteristics can be predicted and precisely interpret by using a two level factorial design and generated quadratic mathematical equation.
Optimization:
Optimization technique is a rational approach for selecting the excipients, their concentrations and process conditions for obtaining the best possible product satisfying the quality characteristics. The word ‘optimize’ can be described as perfect effective or functional. In pharmacy ‘optimization’ is related to formulation or process. Optimization process can be done into three parts
1. Analysis of results-Model
2. Simulatio
3. Response Surface Methods (RSM)
As the design of experiment can be defined as the strategy for setting experiments in the required information is obtained as efficiently and precisely as possible. In this the experiment is conducted with a given number of variables as input and the number of their level and includes the output called as response.
Analysis of result-Model:
The result obtained from the DOE are analyzed in order to draw the conclusion for obtaining the best possible product. Modeling is necessary because the operating conditions in the experiment are far from actual optimum.
Simulation:
In simulation the model is used for predicting the theoretical formulation of all process.
Response Surface Methods (RSM)
1. Central Composite Design
2. Box Behnken Design
3. D-Optimal Design
Central Composite Design:
The central composite design (CCD) is the most frequently used RSM design. It isa factorial or fractional factorial design with centre points, augmented with a group of axial points (also called star points) i.e. A CCD can be divided into 2 parts:
1 Two level full or factorial design (the core)
2 Centre points
The two level factorial design parts consists of all possible combinations of plus or minus one level of factors. Axial points are often represented by stars from the centre point with all but one of the factors is set to 0. The coded distance of the axial points is represented as a plus or minus alpha (α). For a two-factor problem the axial points are (-α, 0), (+α, 0), (0,-α) and (0,+α) After finding the main factors, it is often useful to obtain a more detailed model of a system. There are two prime reasons. The first is for optimization: to find the conditions that result in a maximum or minimum as appropriate. An example is when improving the yield of synthetic reaction. The second is to produce a detailed quantitative model: to predict mathematically how a response relates to the values of various factors. It has been used for the determination of the critical conditions of experimental factors during the optimization of extraction steps, derivatization reactions, separation steps, quantification processes and alsorobustness studies involved in chromatographic methods. A central composite design is the most commonly used response surface design experiment.
Box Behnken Design:
These designs require only three levels code as - 1, 0, + 1. This design created by combining two-level factorial designs with incomplete block designs. This procedure creates designs with desired statistical properties but most important with only a fraction of the experiments needed for a full three level factorial. Box Behnken designs were introduced in order to limit the sample size as the number of parameter grows. The main objective of experimental design is studying the relation between the response as a dependent variable and the various parameter levels.
D-Optimal Design:
The D-optimal criteria is one of the several ‘alphabetic’ optimality’s that was developed to select design points to minimize the variance associated with the estimates of the co-efficient in the model you specify. The design space is defined by low and high level constraints on each factor. You can add multiple linear constraints.
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Received on 08.06.2019 Accepted on 10.07.2019
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Asian J. Pharm. Tech. 2019; 9(3):228-237.
DOI: 10.5958/2231-5713.2019.00038.2