Dear Colleagues; this week, we will review the points to consider when preparing pediatric extemporaneous (magistral) formulations from preparations that may be available in our pharmacies for adults, but not in pediatric doses. Since we may sometimes need to prepare vital drugs in pediatrics that are not commercially available on the market, this subject must be thoroughly understood. I would like to express my gratitude to our esteemed professor Assoc. Prof. Dr. Mesut Arıcı, faculty member of the Department of Pharmaceutical Technology at Ege University Faculty of Pharmacy, for his contributions in sharing this important information with you.
Many children do not like taking medicine, and children’s age, weight, and individual drug requirements naturally differ. Sometimes, sugar-free, gluten-free, casein-free, soy-free, or dye-free medications may be required. There are several methods to make taking medication an enjoyable experience for these children. Preparing medication tailored specifically for a pediatric patient is today an art of extemporaneous compounding; with modern formulation techniques and various flavorings, it is possible to prepare pediatric medications in pharmacies that provide individualized strengths and dosage forms. It is possible to grind divided or crushed tablets with lactose into powder and mix them with ice cream, chocolate syrup, or fruit juices to administer to the child. Preparing a medication in suspension form from these tablets is also an easier and more cost-effective method.
As a result, it may not always be possible to find commercially available medications on the market that suit the individual needs of children. These issues can be resolved through communication between the pediatrician and the pharmacist. Following this communication, the pharmacist can formulate a drug that meets the child’s specific requirements.
Compounding extemporaneous formulations can be beneficial not only for children but also for young or elderly patients.
Medications commonly prescribed for children can be classified as follows;
Pain relievers
Respiratory disorders
Oral thrush
Diabetes
Head lice
Diaper rash
Skin diseases
Skin sores / blisters
And similar conditions.
Many children may need to take multiple medications throughout the day and may experience difficulties, especially swallowing capsules or tablets. To solve these problems, by developing collaboration between the pediatrician and the pharmacist, it is possible to prepare palatable oral formulations containing the child’s preferred flavor.
Special drug dosage forms for children consist of;
Oral liquids
Lollipops
Chewing gum
Topical gels
Effervescent drinks.
Some extemporaneous formulas can be administered to infants using special pacifiers or bottles. In autism, for example, medications containing casein, soy, sugar, gluten, dyes, carbohydrates, and heavy metals (such as aluminum) adversely affect autistic children. The pharmacist must know the medications and foods families purchase for their autistic children and manage dietary restrictions. In magistral formulations, it is always possible to customize different dosage forms and flavors, as well as essential components that are particularly important in autism, such as melatonin, amino acid, and vitamin mixtures, specifically for the child.
In the US, customized formulations for autistic children are frequently prepared in pharmacies, and pharmacists have a dedicated responsibility to develop these formulations and monitor their administration.
As is known, age groups in pediatrics are classified as follows;
Premature infants,
Neonates,
Infants and toddlers,
Preschool children (2–5 years),
School-age children (6–11 years),
Adolescents (12–18 years).
Among these groups, dosage forms similar to adults are generally administered to adolescents; however, lower doses may need to be administered to underweight adolescents.
Tablets or capsules can be administered to school-age children, but parents may prefer orally disintegrating or chewable tablets.
According to guidelines, preschool-age children can use orally disintegrating tablets (they cannot swallow regular tablets and capsules); however, starting from this age group, solution or suspension formulations are preferred. Therefore, European Medicines Agency (EMA) guidelines recommend the use of solution or suspension-type preparations as oral dosage forms for children aged 5 and under.
Sources of active pharmaceutical ingredients (APIs) in formulations;
They are addressed in two ways: bulk active substances and commercial products.
Points to consider when using commercial products in formulations;
1- Certain dosage forms should not be used in extemporaneous compounding (e.g., extended-release preparations, delayed-release preparations).
2- Some excipients in the commercial preparation may affect the stability and bioavailability of the magistral preparation.
3- If injectable preparations are used, the salt form of the active substance must be checked.
4- Some injectable preparations may contain the active substance as a prodrug. Active substances in this form may not exhibit activity when administered via other routes.
Points to consider when using commercial products in formulations;
1- When using an injectable solution in a magistral preparation for oral use, the stability of the drug in gastric fluids, exposure to the first-pass effect, and the taste of the drug must be considered.
2- It should not be overlooked that the shelf life of reconstituted injectable powders can be very short.
3- When using commercial products in solution form, the pH of the final product must be checked. If the pH of the final product is unsuitable, a suspension rather than a solution may have been prepared.
4- The presence of buffers in commercial products may affect the pH of the final product.
5- The cost of magistral preparations prepared from commercial products is higher compared to preparations prepared from bulk active substances.
Pediatric dosage forms;
1- Liquid preparations (such as solutions, suspensions, syrups),
2- Powder preparations (such as capsules, sachets),
3- Parenteral preparations (diluted with sterile water for injection, bacteriostatic water for injection, or 0.9% sodium chloride solution).
One of the most important issues to consider during the preparation of pediatric forms is Stability. One of the most essential factors to consider in the design and development of dosage forms is the stability of the active substance and the product. Stability is one of the key quality indicators. The durability of a drug means that its properties at the time of manufacturing remain within predetermined limits throughout production, storage, transportation, storage in the hospital or pharmacy, and the period of use. The manufacturer is primarily responsible for ensuring the stability of the marketed product. Additionally, the pharmacist who dispenses and compounds the medication is obliged to know the stability characteristics of the drug and convey this information to the patient.
To recall the types of stability;
1- Chemical,
2- Physical,
3- Microbiological,
4- Therapeutic,
5- Toxicological.
Chemical stability; Each active substance must maintain its chemical integrity and stated potency within predetermined limits. Knowledge of selecting storage conditions (temperature, light, humidity), appropriate containers (glass or plastic, colorless, amber, or opaque), and potential interactions (incompatibility) when active substances or dosage forms are mixed is crucial for chemical stability. Stability and beyond-use date information is based on reaction kinetics (rate of chemical change studies). The most common chemical degradation mechanisms are hydrolysis and oxidation.
Hydrolysis: The formation of products with different chemical structures as a result of the active pharmaceutical ingredient reacting with water (e.g., the formation of one molecule of salicylic acid and one molecule of acetic acid resulting from the hydrolysis of aspirin with water).
Oxidation: Most oxidative changes in pharmaceutical preparations occur in the form of autoxidation. It occurs spontaneously under the initiating influence of atmospheric oxygen. It initially proceeds slowly, but later accelerates.
Factors affecting chemical stability:
1- pH
2- Temperature
3- Solvent
4- Light
5- Air (oxygen)
6- Carbon dioxide
7- Humidity
8- Particle size
Physical stability; Maintenance of original physical properties (such as appearance, taste, homogeneity, dissolution, and dispersibility). To summarize;
Loss of physical stability occurs through:
1- Polymorph formation,
2- Crystallization,
3- Evaporation,
4- Adsorption.
Microbiological stability; Maintenance of sterility or resistance to microbial growth within predetermined limits, especially in liquid and semi-solid dosage forms (solution, suspension, emulsion, cream, ointment). Antimicrobial agents added to the product to prevent microbiological growth must maintain their efficacy within predetermined limits. For parenteral products, sterility must be maintained throughout the shelf life.
Therapeutic stability; The therapeutic effect remaining unchanged. Excessive changes in chemical, physical, and microbiological stability affect the therapeutic efficacy of the preparation. For example, the crystal form and consequently the dissolution properties of an active substance exhibiting polymorphism may change depending on storage conditions.
Toxicological stability; No significant increase in toxicity occurs. If the active substance is not sufficiently stable and the resulting degradation products are more toxic than the active substance, or if the degradation products of excipients are toxic, toxicological stability is considered compromised.
Beyond-use date for preparations without published stability data (USP)
Various guidelines have been defined for non-sterile compounded preparations regarding the maximum recommended beyond-use date, provided they are packaged in tight, light-resistant containers and stored at controlled room temperature unless otherwise specified.
Beyond-use date for non-aqueous liquids and solid formulations: If a commercial drug is used as the source of the active ingredient(s), the beyond-use date cannot exceed 6 months or 25% of the time remaining until the commercial product’s expiration date, whichever is shorter. When preparing a formulation starting from active ingredient(s) meeting pharmacopeial specifications, this period cannot exceed 6 months.
Beyond-use date for water-containing formulations: When the preparation is compounded from solid active substances, the beyond-use date is 14 days when stored in a refrigerator. For all other formulations: the beyond-use date is shorter than 30 days or equal to the intended duration of therapy.
Returning to our formula;
Rp.
Propranolol hydrochloride 500 mg
Citric acid monohydrate 1 g
Sodium benzoate 100 mg
Syrup 40 ml
Purified water to 100 ml
Substances included in the formula;
Propranolol hydrochloride – Propranololum hydrochloricum – Propranololium chloratum;
Propranolol hydrochloride is a white or almost white, odorless crystalline powder. It is soluble in water and alcohol; slightly soluble in chloroform; practically insoluble in ether. In aqueous solutions, it decomposes via oxidation of the isopropylamine side chain, resulting in a drop in pH and discoloration. The most stable pH for its solutions is 3; it decomposes when the pH turns alkaline. Propranolol tablets and solutions should be stored at room temperature of approximately 15°C, protected from light and moisture. Solutions must not be frozen. Propranolol is administered via oral or intravenous (IV) routes. Propranolol is primarily eliminated renally as metabolites. Only 1-4% is excreted unchanged in the feces. Propranolol exerts receptor blockade. Among the most important of these resulting pharmacodynamic effects are reducing heart rate both at rest and during exercise, and lowering systolic and diastolic blood pressure. Propranolol can attenuate reflex orthostatic hypotension. Propranolol also competitively blocks receptors located in bronchial and vascular smooth muscle and carries the potential to induce bronchospasm. The reasons propranolol is beneficial in treating hypertension include reducing heart rate at rest and after exercise (negative chronotropic effect); its negative inotropic effect leading to reduced cardiac output; decreasing sympathetic outflow from the central nervous system; and suppressing renin secretion from the kidneys. Thus, like other beta-blocker drugs, propranolol affects blood pressure through several different mechanisms. Propranolol is also used in the treatment of portal hypertension and prevention of esophageal variceal bleeding. Numerous factors may contribute to the efficacy of propranolol in preventing migraine headaches. Propranolol can eliminate the peripheral physiological symptoms seen in anxiety.
Citric acid monohydrate – Acido del Limón – Hydrous Citric Acid – Acidum Citricum Monohydricum;
Citric acid and sodium citrate are alkalinizing agents used orally. Citric acid is also used as an excipient in pharmaceutical technology for preparing effervescent granules, solutions, and syrups.
Sodium benzoate – Sodii benzoas – Natrium benzoicum;
Sodium benzoate occurs as a white, odorless or almost odorless, granular or crystalline powder or flakes. According to the British Pharmacopoeia (BP), it is a slightly hygroscopic substance. Solubility according to BP: Freely soluble in water; sparingly soluble in alcohol (90%). Solubility according to the United States Pharmacopeia (USP): Soluble 1:2 in water, 1:75 in alcohol, and 1:50 in 90% alcohol. Sodium benzoate increases the secretion of bronchial mucous glands reflexively by irritating the gastric mucosa and/or by direct action. For this reason, it is incorporated into the composition of most cough formulations.
Purified water – Distilled water – Pure water
Preparation of the formula;
Propranolol hydrochloride tablets can be used in the formula. The tablets and solid substances are thoroughly ground in a mortar, and then syrup is added to form a paste. The formula is finalized by gradually adding the calculated amount of water. Propranolol tablets containing calcium carbonate as an excipient should not be used. It should be stored at 2–8°C. It must be consumed within 28 days from the date of preparation.
Wishing you a pleasant week…
References
Assoc. Prof. Dr. Mesut Arıcı, Lecturer at Ege University Faculty of Pharmacy, Department of Pharmaceutical Technology
Australian Pharmaceutical Formulary and Handbook 21st Edition
Specialist Pharmacist Ahmet Nezihi Pekcan
Pekcan Pharmacy – Konya
[email protected]
Tel: (332) 3520657
http://www.majistralformul.com/
