Chapter Two — Literature Review of Clobetasol Propionate.
Preface
THIS WILL BE PUBLISHED PER CHAPTERS: PART 2/8.
During my final year of my bachelor of pharmacy I had the joy of doing a project in pharmaceutics on topical corticosteroids. My colleague and I achieved a distinction for this project but we do admit that we can see some mistakes in our project. This project took us 6 months to accomplish and it mainly taught us about research, reading the literature and to attempt at making a pharmaceutics project. This was more of an introduction to a masters degree path and also taught us to work on our own and be supervised with an allocated supervisor. All in all, we learned a great deal and we were thankful for it.
Authors: Andréas L.P. Astier, Priyanka Naidoo
Supervisors: Professor R. Walker, Dr S.M. Khamanga
Location: Pharmaceutics department, Rhodes University, Grahamstown, 6140, South Africa.
CHAPTER TWO
Literature Review
Topical corticosteroids are formulated for the treatment of dermatoses (34). These types of formulations vary in efficacy due to the factors on which such efficacy is dependent. Concentration, occlusion, the vehicle, added penetrants, surfactants and the amount of absorption affect the efficacy and aesthetic appeal of the formulation. These factors are, however, only a part of a chain of elements that affect the stability, efficacy, the textural and microbial profile of the formulation. The manufacturing methods, conditions and combinations of materials are what define the above-mentioned aspects of a final formulation. Within a pharmacy setting, manufacturing methods are simplified. This affects the profile of final formulation and will thus have either a pleasing or displeasing aesthetic appeal to the patient for which it is intended, due to the manufacturing practice that has been established within such an environment (34).
Drugs applied topically act either locally at the surface of the skin or at the stratum corneum (35). These drugs may also modulate the function of the dermis or epidermis. The formulations found in these categories are creams, ointments, pastes, gels, suspensions, foams, aerosols and lotions. These formulations are termed topical dosage forms and exclude transdermal patches. These topical dosage forms can be further classified as a colloid, suspension, emulsions, semisolids, solid or spray (36).
In the pharmacy setting, corticosteroids are diluted with a base either to produce a cream formulation or an ointment formulation. For the purpose of this study, the compounding of topical semisolid formulations such as ointments and creams will be reviewed. The dilution of topical corticosteroids is common practice around the world and is usually in response to a request by a physician (35). The general expectation of these dilutions is that activity of the corticosteroid formulation is reduced to be of a better design for the intended patient’s condition and dose requirements (35). For these purposes, well-known corticosteroid molecules are prescribed but the degree of reduction in the activity of these molecules is not easily determined (35). This makes the practice of dilution of topical corticosteroids dangerous due to the risk of accelerated chemical and physical decomposition, microbial contamination and interference with the biopharmaceutical profiles of the manufactured formulation (35). There is thus much controversy surrounding the dilution of topical corticosteroids. This will ultimately present an issue in terms of adherence to treatment and the patient’s perceptions of the acceptability of the formulation given to them.
Due to the sophisticated nature of commercially available bases, changes in the concentration of components of the base may present an effect on the rate of release of the corticosteroid from the final formulation (35). The Dilution of topical corticosteroids, therefore, creates the potential to result in a disturbance of the equilibrium of components in the base that are necessary for the release of active ingredients (API) (35). For a drug to exert an effect in a topical semisolid formulation, it must diffuse out of the vehicle in which it is incorporated and onto the skin surface where it must then permeate through to the intended site of action (35). The liberation of the drug is however affected by the type, composition and rheological properties of the vehicle used in the dilution of the formulation as well as the solubility of the drug placed in the final formulation (35). In any form of pharmaceutical manufacture, whether it be in the pharmacy or at a facility, the most suitable choice of vehicle or base is therefore vital. The choice of base is decided based on the desired action required, nature of the medicament and the associated stability and bioavailability thereof, the required shelf life needed for the formulation and the rate of release desired over the period of time for which the formulation is intended for use (37). The base that provides the greatest stability to the final formulation must be used. For example, when using an API that hydrolyses rapidly, a hydrocarbon base is more appropriate than water containing base despite the greater effectiveness of the latter option (36).
CBP is a fluorinated corticosteroid. It is a white, crystalline, odourless powder with a solubility of 2g/ml. at room temperature and 10g/ml in alcohol (37). Formulations made with this API are potent. At the usual dosage, small amounts reach the dermis and systemic circulation but when the skin is inflamed or diseased, penetration is enhanced and absorption is increased (37). CBP is therefore used for short term relief of pruritic and inflammatory manifestations. CBP is therefore applied as a thin film, twice daily in its topical semisolid form as either a cream or an ointment. When applied, CBP will produce an effect despite the vehicle, but the effects and availability of the API will be more pronounced from one vehicle than the other. In a study analyzing the pharmaceutical availability of clobetasol-17 propionate from a cream and an ointment, CBP was shown to have a better availability in cream than in an ointment (37). CBP ointment was prepared using a Vaseline base and CBP cream was prepared using an oil-in-water emulsion base (37). The rate of release was measured using HPLC at a wavelength of 254nm and samples were taken at various time intervals (37). The changes in the concentration of both formulations were interpreted based on a pseudo-first-order equation (37). The end results reflected a greater availability and therefore rate of release, from a cream (37). This leads to the conclusion that the choice of base or vehicle impacts the rate of release of API.
In another study, it was shown that there are even a release rate and viscosity variability between different cream bases (38). CBP was incorporated into different two creams each containing different components (38). Viscosity was tested using a cone and plate viscometer and in vitro release was tested using a Franz diffusion cell and artificial membrane (38). Skin blanching tests were also performed on six healthy male volunteers, aged 24 to 27, and who presented with no prior history of skin disease (38). The results of the study showed the CBP creams to have varying viscosities with cream A as a lower viscosity resulted at all temperatures (38). Cream B displayed near-constant viscosity at all temperatures but upon analysis was shown to bear unfavourable conditions during long term storage (38). In terms of release rates, both creams displayed slow release in the beginning but after time cream A showed the highest release rate and cream B showed the lowest release rates (38). The results of the skin blanching and colourimetry tests further affirmed this (38). Each cream was tested at two different durations with a short duration of 0 to 8 hours and a longer duration of 0 to 48 hours (38). This shows that the difference in formulation components of cream bases can also affect the availability of an API hence the most suitable choice of base is important when manufacturing or compounding.
These two studies demonstrate the importance of choosing the correct base for the incorporation of the drug or API.
2.1. Rheological properties
Rheological properties of an aqueous system are determined by the degree of emulsification of the formulation. When oil-in-water aqueous systems contain a surfactant or fatty alcohol combinations, an additional phase forms when the emulsifier is more than that amount required to form a monomolecular film at the oil droplet interface (39). The resulting interaction with continuous phase (water) forms a gel network of vastly swollen bilayer structures (39). This swollen network thus results in the rheological properties of the cream (39). In an emulsion containing a non-ionic surfactant and fatty alcohol hydration of the polyoxyethylene chains of the interpositioned surfactants that are orientated and extended into the interlamellar, cause swelling of the bilayers (39). The rheological properties and swelling behaviour of an aqueous cream are thus proportional to the surfactant polyoxyethylene chain length (39).
For a water-in-oil emulsion, the nature of the emulsion tends to be greasy due to the external phase being primarily oil (40). These formulations are ointments. The discontinuous phase of water repels any action associated with water (40). A water-in-oil emulsion is formed if the aqueous phase constitutes less than 45% of the total weight of the formulation and also if a lipophilic emulsifier is used (40). Water-in-oil- emulsions are stabilized by surfactant films (such as resins) that behave like hard-sphere dispersions which display viscoelastic behaviour (41). Water-in-oil emulsions show predominantly elastic properties (41). There is a definite transition from viscous to elastic response thus creating viscoelasticity (41). This viscoelastic nature displays increasing steric interaction with increases in the volume of the discontinuous phase (41).
Rheological properties also consist of viscous, elastic and plastic properties as seen from the above. Viscoelasticity, however, the most important of the properties for semisolids as semisolids combine solid behaviour and liquid properties in one formulation (42). Viscoelasticity is defined as the simultaneous existence of viscous and elastic properties. The application of stress on the formulation and the duration of stress is used to determine the parameters for rheology and provide information on the intermolecular and interparticle properties of the formulations (42).
2.2. Surfactants
Surfactants affect the rheological properties of topical semisolids whether they are used singly or in combinations with other surfactants (42). It has however been found that combinations of surfactants are often more effective in cream stabilisation than the use of a single surfactant (42). The blend of surfactants in an aqueous system creates tighter packing between the phases formed (42). This, therefore, contributes to the strength of the surfactant film and thus to the stability of the formulation. In a pharmacy setting, consideration may be made towards this if there is a need to enhance the stability of the formulation.
During the development of a formulation, the type of emulsifier, the hydrophilic-lipophilic balance value and the solvent to emulsifier ratio must be taken into account to produce a stable emulsion (43). An appropriate emulsifier system is needed to create to the dispersion of the drug into the containing solvent phase so that an emulsion (O/W or W/O) can be created (43). The charge of the surfactant should also be taken into account as it can cause instability within the formulation if the charge of the surfactant and the charge of other excipients repel. For example, charge interactions between an anionic surfactant and a positively charged drug or vice versa can cause instability or an anionic emulsifier with monovalent salt may be inactivated by multivalent counterions (e.g., Ca++, Mg++) (43).
2.3. Instability mechanisms and emulsion stability in topical semisolid formulations
When manufacturing or compounding a formulation, various instabilities can result from the incorrect formulation. These are important to note when designing formulae and choosing combinations of excipients for the formulation of topical corticosteroids in the pharmacy setting.
Emulsions are deemed to be inherently thermodynamically unstable (44). It is therefore important to consider the sources of emulsion stability or instability. Sources that affect the instability of an emulsion are coalescence, creaming and flocculation. These processes can be demonstrated by taking an emulsion with limited stability and centrifuging it at low speeds along with various times periods (44).
2.3.1. Coalescence
Coalescence is the process by which an emulsion completely breaks (44). The system separates into different phases namely the bulk oil and water phases (44). The process of coalescence is considered to be governed by four different droplet loss mechanisms (44). These mechanisms are Brownian flocculation, creaming, sedimentation flocculation and disproportionation. The first three mechanisms are the main mechanisms which cause destabilization however, all four processes can occur simultaneously and in no specific order (44). The process of coalescence can be characterised by a cream rising when an oil with a density less than water is present (44). As the larger droplets rise and concentrate, they begin to appear at the top of the formulation (44). The drops then coalesce to form a separate layer of oil on top (44). Ointments tend to display to coalescence instead of creaming (44).
2.3.2. Creaming
Creaming is a separation of an emulsion into two emulsions (44). one emulsion is richer in the disperse phase than the other. Creaming is, therefore, the process whereby the disperse phase separates from an emulsion (44). Creaming is thus seen as the precursor to coalescence (44). Creaming is inhibited by a small droplet radius, a highly viscous continuous phase and a low-density difference between the oil and water phases (44). This is evidenced by stokes Equation (44):
𝑣=2𝑟% 𝜌−𝜌( 𝑔/9ɳ
𝑉 = 𝑐𝑟𝑒𝑎𝑚𝑖𝑛𝑔/𝑠𝑒𝑡𝑡𝑙𝑖𝑛𝑔
𝑅 = 𝑟𝑎𝑑𝑖𝑢𝑠 𝑜𝑓 𝑑𝑟𝑜𝑝𝑙𝑒𝑡
𝜌 = 𝑑𝑒𝑛𝑠𝑖𝑡𝑦 𝑜𝑓 𝑑𝑟𝑜𝑝𝑙𝑒𝑡
𝜌( = 𝑑𝑒𝑛𝑠𝑖𝑡𝑦 𝑜𝑓 𝑡h𝑒 𝑑𝑖𝑠𝑝𝑒𝑟𝑠𝑖𝑜𝑛 𝑚𝑒𝑑𝑖𝑢𝑚 ɳ = 𝑣𝑖𝑠𝑐𝑜𝑠𝑖𝑡𝑦 𝑜𝑓 𝑡h𝑒 𝑑𝑖𝑠𝑝𝑒𝑟𝑠𝑖𝑜𝑛 𝑚𝑒𝑑𝑖𝑢𝑚 𝑔 = 𝑙𝑜𝑐𝑎𝑙 𝑎𝑐𝑐𝑒𝑙𝑎𝑟𝑎𝑡𝑖𝑜𝑛 𝑑𝑢𝑒 𝑡𝑜 𝑔𝑟𝑎𝑣𝑖𝑡𝑦
2.3.3. Flocculation
Flocculation is the aggregation of droplets that result in 3-D clusters (44). Flocculation is the result of a weak, net attraction between droplets (44). Coalescence does not occur in flocculation and all droplets maintain their own integrity and remain as separate entities (44). Flocculation may even be further divided into two categories (44). The first is flocculation resulting from sedimentation aggregation the second is flocculation resulting from Brownian motion aggregation of the droplets (44). In polydisperse emulsions, creaming of different-sized droplets occurs at different rates (44). This results in a tendency for collision with and trapping of slower-moving smaller droplets by faster-moving (larger) ones (44). For the above-mentioned categories, the difference between the two arises from the assumption that all the paths in sedimentation aggregation are vertically linear whilst Brownian aggregation is due to the random Brownian movement of the droplets (44). Both these processes can occur simultaneously in a typical emulsion and therefore cannot be rigorously separated (44).
Flocculation may also be divided into fast or slow flocculation (44). Fast flocculation occurs when smaller droplets disappear faster than larger ones due to the different rates of movement that occur under the influence of gravity or forced convection (44). This leads to an increased collision rate otherwise known as orthokinetic aggregation (44). Slow flocculation occurs when there is a resultant build-up of large metastable structures that slow due to the energy barrier between droplets, and the formation of droplet-free spaces between aggregates and the heavier aqueous phase O/W emulsions (44). The process occurs respectively in that order and the result is termed hindered creaming (44).
2.3.4. Disproportionation or Ostwald ripening
This is a process that results due to the diffusion of disperse phase molecules from smaller to larger droplets through the continuous phase (44). The pressure of dispersed material is greater for smaller droplets than larger droplets (44). The pressure differential that exists between the small and large droplets produces a driving force for the diffusion to occur (44). The rate of diffusion will, however, depend on the solubility of the dispersed phase in the continuous phase (44). The greater the disperse phase volume then the greater the relative vapour pressure and thus solubility will be (44).
2.4. Production assessment
To assess the effect of these dosage forms, product quality and performance tests must be conducted to assess the drug release, content uniformity, pH, microbial limits and also the physiochemical identity of the formulations (36). Due to the variation in the physical properties of these formulations, product testing is must also test the rate of drug release and thus its efficacy is affected by these properties (36). As a result, the method of in vitro testing and thus the apparatus to be used will differ amongst the formulations. Currently, product performance test exists for semisolid formulations such as creams and ointments (36). The apparatus and methods used for this type of testing is the vertical diffusion cell (VDC), USP apparatus 5 and high-performance liquid chromatography (HPLC) (36). The first two systems are the two most simple systems known to yield reliable and reproducible results when operated correctly (36).
2.4.1. In vitro testing
To ascertain the drug release from a formulation, performance testing must be employed (36). Performance testing is not a test of bioavailability but should indicate changes in the drug release characteristics from the final formulation as drug release characteristics can affect the biological performance of an API (45). Changes that can occur may arise from the active or inactive/inert ingredients, the physical or chemical attributes, the manufacturing variables, shipping and storage effects, aging effects, and other factors of the final formulation (45). The most popular performance tests are as mentioned above; the vertical diffusion cell method, high-performance liquid chromatography (HPLC) and USP apparatus 5 (paddle over disk) (36). Dissolution testing is thus an important tool in drug development and quality control of pharmaceutical products. This type of testing was initially intended for immediate release and modified release solid oral dosage forms but recently has become useful in the testing of the novel or special dosage forms such as creams, ointments and gels, to provide a method to characterize the in vitro release of drug from these formulations (45). For the release of drug from novel dosage forms, the term “drug release” or “in vitro testing” is used. Since novel/special dosage forms possess different characteristics from immediate and modified release solid oral dosage forms, carefully designed methods need to be instated (45). Consideration must be made towards the site and mode of administration, apparatus selected for testing, the composition of the dissolution medium, agitation or flow rate and temperature (45). For the determination of this, compendial apparatus and methods are the first approaches when deciding the design of the in drug release or in vitro testing (45).
2.4.2. Franz cell diffusion system or vertical cell diffusion system
In vitro testing has been extensively conducted through the use of a vertical diffusion cell system, otherwise known as a Franz cell diffusion system, and a synthetic membrane and to some extent, the enhancer cell (45). The two types of apparatus used were shown to generate similar data however, limited data is available with the enhancer cell system and it lacks collaborative or validation data (45). During in vitro testing, the sample weight or volume to be used should reflect the typical dose of the formulation prescribed by the physician (45). The receptor medium in which the semisolid dosage form is placed may need to contain alcohol and or a surfactant depending on the solubility of the drug substance (45). A partial dose may be used and may even be preferable as opposed to the addition of a surfactant or alcohol to the receptor medium to obtain sink conditions (45).
Next, an important note should be taken of de-aeration (45). The formation of bubbles at the interface with the membrane should be avoided (45). A synthetic membrane is often used and serves the purpose of acting as an inert support membrane, but depending on the characteristics of the drug product, a synthetic support membrane may not be necessary (45). Such an example to illustrate this are tests done on some ointments using the Franz cell. Tests for these ointments were done both with and without membranes (45). This resulted in no difference in the release rate results (45). The release characteristics tend to follow the Higuchi model which a model that quantifies drug release from thin ointment films that contain the finely dispersed drug in a perfect sink (46). The test temperature should typically be set at 32°C as this reflects the usual temperature of the skin but deviations in this temperature may be instated due to the specific sites of action the semisolid may act on (45). The vertical diffusion cell is often chosen due to its to be simplicity and reliability. It provides a reproducible method of testing drug release of topical semisolid formulations.
2.4.3. USP apparatus 5
Transdermal drugs can also be assessed for performance or drug release using USP Apparatus 5, Apparatus 6, or Apparatus 7 (47). USP Apparatus 5 however, is the simplest method of testing that can be employed to test most types, sizes, and shapes of transdermal delivery systems (47). Such systems include transdermal patches, ointments, floaters and emulsions (47). The Paddle over disk apparatus simulates fluid motion otherwise known as hydrodynamic motion. The pH of the medium should be 5 to 6 and should be adjusted if need be (45). A buffered solution should be used to maintain conditions. Water is therefore not an ideal medium as it cannot buffer itself. The test temperature should typically be 32 ±0.5°C (45). These conditions are meant to reflect the physiological conditions of the body. During the test, a distance of 25+2 mm should be maintained between the paddle blade and the surface of the disk assembly (45). The assembly of the disk is designed to minimize any dead volume between the disk assembly and the bottom of the vessel (45).
2.5. Product quality testing
Product quality testing in the large scale manufacture is unavoidable. Manufacturers are required to perform product quality testing due to laws placed upon them by regulating bodies. In the community pharmacy setting, these tests are not required but due to the act of extemporaneous compounding, the premise behind certain tests should be considered as various factors affect the overall stability, microbial and textural profile of the formulation. The general tests stated by the United States Pharmacopoeia are the following; description, identification, assay, physiochemical properties, uniformity of dosage units, water content, microbial limits, antimicrobial preservative content, antioxidant preservative contents, Sterility, pH, particle size and viscosity (36). These tests, analyse and assess exactly what their titles suggest. Due to there being numerous tests, not all can be considered (36). The tests most applicable to topical dosage forms are the viscosity, content uniformity, pH and particle size (36). Each of these tests and their applicability to the pharmacy environment are explained below.
2.5.1. Viscosity
Viscosity has a direct effect on the rheology of a formulation and thus the rate of release of the drug and the overall drug delivery (36). Viscosity affects the diffusion of the drug at a microstructural level but despite this, semisolid formulations may still possess the ability to exhibit high diffusion even with a high viscosity much the same as a semisolid formulation of lower viscosity (36). The unpredictable effects of viscosity on the rate of diffusion of the drug is thus an important consideration when choosing a suitable vehicle in which the drug will be incorporated.
Due to the effect of viscosity on rheological behaviour, the site of application and the consistency of the treatment and dose delivered are affected (36). At this stage of compounding it becomes essential to maintain the reproducibility of the formulation’s flow properties or behaviour the time of release which begins soon after the completion of compounding (36). Consistency, therefore, becomes key in maintaining constant drug release (36). When applied strain is placed on a non-Newtonian liquid, shear-thinning i.e. the decrease in viscosity occurs (36). Most semisolid dosage forms display non-Newtonian behaviour when sheared (36).
This becomes an important factor in the compounding of topical corticosteroids as the correct combinations of API, excipients and base must be chosen to avoid inconsistencies in viscosity, due to the structures formed within semisolid drug products during manufacturing or compounding (36). A range of behaviours can occur from these structures and these include not only shear-thinning viscosity but also thixotropy and structural damage (irreversible or only partially reversible) (36). Viscosity also affects the spreadability, application rate and shelf-life under extensive shear (36).
In addition, the viscosity of a semisolid dosage form is highly influenced by such factors as the inherent physical structure of the product, temperature and container size and shape, therefore all of the above factors should be taken into consideration when compounding (36). The regulation of temperature in the pharmacy setting should also be maintained and the selection of containers used to keep formulations in should be chosen wisely to present the patient with the most efficacious formulation possible. As a side note, these last factors may seem negligible or of little concern but in the treatment of patients or a living being, the attention to such detail amounts not only to good quality product design but also ethical treatment and concern.
In the same study Fang et al, the rate of release of CBP from cream A and B was dependent on the viscosity of the creams which also shows the impact of rheological properties. The rate of release was faster from cream A which had a lower viscosity and slower for B which had a higher viscosity (38).
2.5.2. pH
due to the various components incorporated into a vehicle or base, the potential for pH instability is present (36). Semisolid drug products should be tested for pH changes. Since most semisolid dosage forms contain very limited quantities of water or aqueous phase, pH measurements may be warranted only as a quality control measure where appropriate such as in large scale manufacture (36). However, pH should be taken into consideration when choosing appropriate combinations of API, excipients and vehicle.
2.5.3. Content uniformity
This refers to the degree of uniformity of the amount of drug in the vehicle (36). Topical semisolid formulations can display physical separation at accelerated storage temperatures due to emulsions, creams, and topical lotions being prone to mild separation because of the nature of the vehicle (36). If the drug content of the formulation is not uniform, then this affects the release of the drug and the amount of drug present at a site of application and percutaneous absorption. In compounding in the pharmacy setting, uniformity of content is important when incorporating API to achieve a safe and efficacious formulation.
2.5.4. Particle size
The particle size of the API is determined during the formulation development stage. Particle size can also be controlled at this stage (36). The size of the API particles in the vehicle determines its dissolution and diffusion rate within the vehicle as well as the rate of percutaneous absorption (36). If an API is not adapted in terms of particle size during the compounding process, then the integrity and/or performance of the final formulation could be compromised. Homogenisation thus also becomes important at this stage as a method of particle size reduction. In many pharmacies, automated homogenisers are used to uniformly mix topical formulations. The use of a homogeniser will affect the size of large particles as well as the viscosity of the formulation. Homogenisation by hand gives a less uniform reduction in particle size but is a method of particle size reduction nonetheless. It is also important to note that the use of certain instruments and production methods can influence the performance of a formulation.
2.5.5. Microbial limits
For many topical semisolid formulations, microbial degradation must be avoided (36). These limits can be tested and are usually based on the nature of the drug substance and bases used for incorporation (36). Microbial contamination or degradation can, however, be avoided through the use of a preservative. This is especially important for a topical formulation that is emulsified as they possess the potential for contamination by various bacteria (48). Hence, antimicrobial preservatives that are often used for generic semi-solid products are methylparaben and propylparaben (48). Chlorocresol is also often used as a preservative. Preservative concentrations are typically used in a range from 0.01% to 0.3% (48).
2.6. Production parameters
The methods employed to compound, manufacture or dilute topical corticosteroids can also affect the stability profile of the formulation. A study conducted on the impact of manufacturing variables on the in vitro release of CBP from pilot-scale cream formulations showed the effect of different homogenization speeds and times, anchor speeds and cooling times on the viscosity and cumulative percentage of CBP released per unit area, at 72 hours from the pilot-scale creams (49). The results were compared to the innovator product known as Dermovate® Cream (49). In this study, thirty pilot-scale batches of creams were formulated (49). Contour and three-dimensional response surface plots were produced and the viscosity and cumulative percentage of CBP released per unit area at 72 hours, was found to be impacted namely by homogenization, and anchor speeds (49). An increase in the homogenization and anchor speeds appeared to exhibit a synergistic effect on the resultant viscosity (49). Viscosity was measured using Brookfield-Model-RVDIþ Viscometer and in vitro release was measured using a Franz diffusion cell system (49). The results of the study yielded a range of 10 800 and 81 566cP for the viscosity of the formulations and a range 42.22% to 68.89% for the cumulative percentage for drug released over a period of 72 hours (49). The use of different manufacturing variables such as homogenization, anchor speeds and cooling times clearly displays an effect on the formulations produced and the different physical properties, release profiles and performance of the drug (49).
From the above study, homogenization speed had the greatest impact on the formulations’ performance (49). The data showed that when the homogenisation speed was increased, the viscosity increased and the cumulative percentage of CBP released per unit area, decreased (49). This study highlights how not only the components of the formulation impact the performance of it but also how the process of manufacture plays a role. It is therefore important to choose the best manufacturing practice for production or compounding to create a formulation that is stable and efficacious.
From all of the above, we can see that there are many factors to take into account when compounding topical semisolid formulations. Factors that influence the compounding or manufacturing process and factors that are a result of manufacture can easily impact the stability, textural and microbial profile of a final formulation. This is why it becomes of vital importance to eliminate these factors from the process of manufacture to create a final formulation that is safe, efficacious and of good quality.
Published 1st August 2019. Last reviewed 30th December 2021.
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