The importance of physician-pharmacist communication in magistral prescription writing (II)
Hydroquinone:Hydroquinone is used topically to produce depigmentation in the skin. It reduces the content of melanocytes in the skin. Structurally, it is similar to monobenzone, a potent depigmenting drug. The difference from monobenzone is that the depigmentation it produces is reversible. In cases of cutaneous hyperpigmentation, it provides temporary lightening of the affected area. Its creams are generally used in treatment. It must be used regularly for weeks for its effect to become visible. Its effect may disappear 2–6 months after treatment is discontinued. The area where the preparation is applied must be protected from sunlight. Therefore, it is usually combined with another sunscreen agent in its preparations. Patients using preparations that do not contain sun protection must additionally use a sun protection preparation. It should not come into contact with the eyes as it may cause eye irritation. Application to large areas of the skin should be avoided as it may cause systemic toxicity. Hydroquinone is a substance sensitive to oxidation. Therefore, it should be used in combination with an antioxidant. The optimum stability of hydroquinone is in the acidic range. In formulations containing hydroquinone alone, prescribing and compounding it with active ingredients that will prevent oxidation should be preferred.Formulation example 1 (2% hydroquinone cream)
Rp.
Hydroquinone 0.5 g
Citric acid 0.05 g
Ascorbic acid 0.125 g
Distilled water (30 °C) 8.25 g
Emulgade® 1000 Ni 2.4 g
Octyldodecanol 1.6 g
Propylene glycol 3.75 g
Distilled water ad 25.0 gEmulgade® 1000 Ni, included in the formula under its trade name, is a mixed emulsifier. Octyldodecanol, another substance in the formula, is a solvent used in pharmaceutical preparations. It essentially consists of 2-octyldodecanol and small amounts of similar alcohols. It is practically insoluble in water; soluble in alcohol and ether.
In preparing the formula, hydroquinone is first dissolved in water with gentle heating. Citric acid and ascorbic acid are weighed, added to this solution, and dissolved. The lipophilic phase is prepared by mixing Emulgade® 1000 Ni and octyldodecanol with propylene glycol and the remaining distilled water in a water bath previously heated to 80 °C. The lipophilic base removed from the water bath is cooled to room temperature by stirring with a high-speed mixer. Meanwhile, the aqueous hydroquinone solution containing hydroquinone, citric acid, and ascorbic acid is added to the lipophilic base brought to room temperature and mixed. Ascorbic acid acts as an antioxidant while also maintaining the acidity of the medium, thereby preserving the ketone structure of Hydroquinone. The finished product is filled into an aluminum tube if possible. Formulations containing hydroquinone should be stored in the refrigerator. The shelf life is six months.
To ensure the chemical stability of hydroquinone, it is necessary to work in an acidic medium. The lipophilic component used, octyldodecanol, is not considered an oil due to its chemical properties; it is an alcohol with oily characteristics. There is also no ester-structured substance as a preservative; only substances that show full efficacy at acidic pH values are included in the formula. Here, propylene glycol was chosen as a pH-independent preservative.
Minoxidil:Minoxidil was initially used only as an antihypertensive agent (Lonolox1 “) and began to be used in the treatment of alopecia areata after it was observed to cause hair growth on certain parts of the body as a side effect. In European countries, alcoholic solutions of Minoxidil were launched on the market in Germany in September 2000 and were exempted from prescription requirements in 2005; thus gaining over-the-counter status, minoxidil has long been available on the market under the trade name Regaine®and other brand names. In varying concentrations for women and men (5%, 2%), physicians and especially dermatologists prescribe minoxidil-containing formulas in the form of compounded prescriptions. The solubility of the active ingredient is generally problematic.
We see this problem in the examples below.Formulation example 1
Rp.
Minoxidil 5.0 g
Propylene glycol 11.5 g
Ethyl alcohol 70% ad 100.0 g
Formulation example 2
Rp.
Norethisterone acetate 0.1 g
Minoxidil 2.0 g
Ethyl alcohol: Isopropyl myristate ad 100.0 g
Formulation example 3
Rp.
17-a-Estradiol 0.015 g
Minoxidil 2.0 g
Ethyl alcohol (Isopropyl myristate 95.5) ad 100.0 gWhile minoxidil dissolves in ethyl alcohol (96%), it dissolves relatively well in propylene glycol. For optimum solubility, both solvents must be present in a specific mixing ratio to each other. A 2% solution can be prepared at room temperature, while a 5% solution can be dissolved by heating. While physicians tried to increase the effectiveness of the treatment by adding substances such as estrogens and antiandrogenic norethisterone acetate to their prescriptions along with minoxidil, solubility issues inevitably arose.
From this perspective, we see an optimized formulation below:Rp.
Minoxidil 2.0 g / 5.0 g
Propylene glycol
Distilled water / ää 15.0 g
Ethyl alcohol 96% ad 100.0 gThe preparation of the product should be as follows: Minoxidil is first dissolved at room temperature or in a mixture of propylene glycol and 96% ethanol heated to approximately 70 °C, depending on the specified concentration. Then, water is added with stirring at room temperature. Other lipophilic active ingredients should be added to the prepared minoxidil solution. The problem of scalp dehydration due to the ethanol in the formulation leads physicians to add isopropyl myristate to the formula. Naturally, a mixture of ethanol and water can dissolve only very limited lipophilic oils in the formulation. This inevitably leads to turbidity and sediment. A better alternative to isopropyl myristate is octyldodecanol, which is chemically not a fat, but a fatty alcohol. It can be used in concentrations of 10–18%.Salicylic acid:Salicylic acid is one of the most commonly used active ingredients in compounded formulations. It is used for keratoplastic, keratolytic, antimicrobial, and antifungal purposes. Abroad, as an over-the-counter active substance, it is among preparations reimbursed by private health insurances. Salicylic acid is covered by reimbursement ‘in dermatotherapy as part of the treatment of psoriasis and hyperkeratotic eczema (2% salicylic acid)’. Salicylic acid exhibits solubility issues in alcoholic or hydroalcoholic solvents, oils, and other liquids.Formulation example 1
Rp.
Salicylic acid 1.0 g
Estradiol benzoate 0.015 g
Dexamethasone 0.3 g
Isopropanol 35% ad 100.0 gThe problem encountered in this formula is the non-dissolution of the active ingredients. Salicylic acid is soluble in water at 1:460, boiling water at 1:15, alcohol and ether at 1:3, and chloroform at 1:45. Using a high concentration of alcohol instead of 35% isopropanol in this formula will increase the solubility of salicylic acid. However, since a high percentage of alcohol will dry out the skin where applied, adding synthetic oils such as isopropyl myristate or octododecanol to the formula is appropriate. Octododecanol is chemically an alcohol, but it exhibits oil-like properties. Its concentration of use is between 10% and 18%, depending on the amount of isopropanol.
Also present in the formula, Dexamethasone is a white or almost white crystalline powder. It is practically insoluble in water; sparingly soluble in alcohol, acetone, dioxane, and methyl alcohol; slightly soluble in chloroform; and very slightly soluble in ether. The United States Pharmacopeia (USP) specifies the pH of its ophthalmic solution as 5-6.
Estradiol benzoate, on the other hand, consists of colorless crystals or a white or almost white crystalline powder. It is practically insoluble in water; slightly soluble in alcohol and fixed oils; sparingly soluble in acetone. The other two active substances in this sample prescription, estradiol benzoate and dexamethasone, are considered to be lipophilic substances that dissolve along with salicylic acid in the formula. Estradiol benzoate can only be dissolved in 70% ethanol with strong heating. However, high heat may cause the degradation of Estradiol benzoate.
The prescription is optimized as follows:Rp.
Salicylic acid 1.0 g
Estradiol benzoate 0.015 g
Dexamethasone 0.3 g
Octododecanol 10.0 g
Isopropanol 69.08 g
Distilled water ad 100.0 gEstradiol benzoate is first dissolved in isopropanol at mild or moderate heat (below 30°C), and then dexamethasone and salicylic acid are added to continue the dissolution process. Water and finally octyldodecanol are added to the solution.Prescription example 2
Rp.
Salicylic acid 6.0 g
Prednisolone 0.1 g
Oleum Olivarum ad 100.0 gScalp oils containing salicylic acid are supplemented with other active ingredients such as prednisolone, triamcinolone acetonide, or betamethasone 17-valerate. Like salicylic acid, prednisolone does not dissolve in olive oil. Therefore, it should be thoroughly shaken by the user immediately before use. In this case, the finely powdered active substances must be homogeneously dispersed in olive oil. However, it would be more suitable to have both active ingredients in dissolved form in the formulation. For salicylic acid, this problem can be overcome by replacing olive oil with castor oil and/or octyldodecanol. However, glucocorticoids do not dissolve in these oils. To dissolve both active ingredients, it would be appropriate to optimize the formulation as follows.Prescription example 2 (optimized)
Rp.
Salicylic acid 6.0 g
Prednisolone 0.1 g
Ethyl alcohol 96% 10.0 g
Macrogol-8-stearate 10.0 g
Isopropyl myristate 35.0 g
Peanut oil 35.0 gPreparation of the formula: The two active ingredients are dissolved in ethanol. Then Macrogol-8-stearate is melted in a water bath together with isopropyl myristate and peanut oil. This mixture is cooled to room temperature, and the alcoholic solution is added. If turbidity occurs, it should be reheated in the water bath. After stirring, evaporation losses are compensated with ethanol. The solution is stored in an amber glass bottle. The formula can be easily applied to the scalp. Due to the presence of the O/W emulsifier, the patient can easily remove the oily solution from the scalp by washing their hair with warm water.Formulation example 3
Rp.
Clotrimazole 1.0 g
Salicylic acid 2.0 g
Isopropyl alcohol 35% ad 100.0 gIn the formula, salicylic acid in dilute isopropanol creates an environment with a pH of approximately 2-3. In this environment, Clotrimazole is hydrolytically cleaved and is therefore inactive. Salicylic acid should therefore be removed from the formulation and, if necessary, presented in an additional preparation. The alternative Clotrimazole formula should be as follows:Formula example 3 (optimized)
Rp.
Clotrimazole 1.0 g
Isopropyl alcohol 70% ad 100.0 gFor clotrimazole to dissolve better, isopropyl alcohol should be at a higher percentage.
Wishing you a good week…Source:1- Gerd Wolf
Rezepturen
Anschrift des Autors
Dr. rer. nat. Gerd Wolf
Fachapotheker für Offizinpharmazie Robert-Koch-Apotheke Fauviller Ring 1 53501 Grafschaft-Ringen
2- 2-RxMediaPharma®2019 Interactive Drug Information Resource
Exp. Pharm. Ahmet Nezihi Pekcan
Pekcan Pharmacy – Konya
[email protected]
Tel: (332) 3520657http://www.majistralformul.com/
