US Pharm. 2018;43(2):47-48.
Method of Preparation: In order to prepare this formulation, it is essential to precisely calculate the amount of each ingredient required for the total quantity needed. Begin by accurately weighing or measuring out each ingredient to ensure proper ratios are maintained. Combine 50 mL of Ora-Plus and 50 mL of Ora-Sweet, which will serve as the vehicle for this preparation. If utilizing sildenafil citrate tablets, ascertain the necessary number of tablets and place them in a mortar. If tablets are chosen for this formulation, they must be pulverized to a fine powder. Following this, add a small amount of the previously mixed Ora-Plus:Ora-Sweet mixture to the powder and mix thoroughly until a smooth paste forms. Gradually incorporate the remainder of the Ora-Plus:Ora-Sweet mixture until the final volume is achieved, ensuring the mixture is homogeneous. Once mixed, package the preparation in appropriate containers and label as needed.
Use: The oral liquid formulation of sildenafil citrate has shown efficacy in treating pediatric pulmonary arterial hypertension in children where the overall risk-benefit profile of sildenafil is judiciously evaluated and accepted.
Packaging: It is critical to package the final product in tight, light-resistant containers to maintain its stability and efficacy.1
Labeling: Ensure proper labeling that instructs to keep out of reach of children. The preparation must be shaken well before use and information regarding the appropriate discard timeline should be indicated clearly to prevent misuse.
Stability: This preparation has a beyond-use date of up to 91 days under appropriate storage conditions, ensuring its effectiveness throughout this timeframe.1-4
Quality Control: Conducting a thorough quality-control evaluation is vital and may include assessments such as weight/volume accuracy, pH verification, specific gravity measurements, active drug concentration analysis, visual color inspection, rheologic properties evaluation (including pourability), and checks for physical stability such as discoloration, presence of foreign materials, gas formation, or any signs of mold growth.5
Discussion: Extensive studies on the stability of oral liquid formulations of sildenafil have been undertaken, specifically for pediatric applications. The results indicate that sildenafil maintains relative stability when formulated in specific vehicles, typically around an acidic pH of 4 to 5. A commercially available formulation for oral suspension (Revatio) contains sildenafil at a concentration of 10 mg/mL and boasts a beyond-use date of 60 days following reconstitution.
In one pivotal study, compounded sildenafil citrate was formulated in a citrate-buffered solution (0.1 M, pH 4) paired with either a syrup excipient, resulting in a suspension, or a sugar-free syrup excipient, resulting in a solution; both were observed to have pH values approximating 4.2. The resulting formulations, both the suspension and solution, were noted to have a slight pink hue and a fruit flavor profile. While the suspension showed stability over 91 days when stored at both 4°C and 25°C, the solution was only stable for 30 days, potentially due to a non-redispersible sediment forming at the bottom of the container.3
Additionally, research led by Nahata et al. demonstrated the stability of a formulation of sildenafil citrate tablets (Revatio 20 mg) in conjunction with a mixture of 1:1 Ora-Sweet and Ora-Plus at a concentration of 2.5 mg/mL, revealing a stability period of 91 days at both refrigeration (4°C) and room temperature (25°C). Another mixture composed of 1:7 (1% methyl cellulose:simple syrup) at adjustable pH levels between 5.1 to 4.9 also maintained stability for the same duration under identical temperature conditions.4
Sildenafil citrate (C22H30N6O4S.C6H8O7, MW 666.70) appears as a white to off-white crystalline powder, displaying solubility of 3.5 mg/mL in water. This compound is available in tablet form, with strengths of 25 mg, 50 mg, and 100 mg for oral intake. In addition to sildenafil, the tablets contain various excipients including microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, lactose, triacetin, and FD&C Blue #2 Aluminum Lake, which together assist in achieving desired bioavailability and stability.6,7
Ora-Plus serves as an effective oral suspending vehicle, capable of accepting dilution of up to 50% or more with various liquids such as water, flavorings, or syrups while still maintaining its suspending characteristics. It has a pH value of approximately 4.2 and an osmolality of around 230 mOsm/kg, exhibiting thixotropic properties with a viscosity of roughly 1,000 cps at 25°C. The formulation comprises purified water, microcrystalline cellulose, sodium carboxymethyl cellulose, xanthan gum, carrageenan, sodium phosphate, and citric acid among its buffering agents, complemented by simethicone as an antifoaming agent, along with potassium sorbate and methylparaben functioning as preservatives.8
Ora-Sweet syrup is a flavoring vehicle designed for oral extemporaneous formulations that integrates a citrus-berry flavor profile and includes glycerin and sorbitol, which work to prevent the issue of cap lock, frequently encountered with many syrup preparations. This syrup is buffered to maintain a pH of about 4.2, and it carries an osmolality of approximately 3,240 mOsm/kg. The composition includes purified water, sucrose, glycerin, a 5% sorbitol concentration, flavoring agents, sodium phosphate, and citric acid as buffering agents, as well as potassium sorbate and methylparaben to ensure preservation.9
REFERENCES
1. U.S. Pharmacopeia/National Formulary [current revision]. Rockville, MD: U.S. Pharmacopeial Convention, Inc; January 2018.
2. Nahata MC, Morosco RS, Brady MT. Extemporaneous sildenafil citrate oral suspensions for the treatment of pulmonary hypertension in children. Am J Health Syst Pharm. 2006;63:254-257.
3. Provenza N, Calpena AC, Mallandrich M, et al. Design and physicochemical stability studies of paediatric oral formulations of sildenafil. Int J Pharm. 2014;460:234-239.
4. Nahata MC. Extended stability of morphine and sildenafil for oral use in infants and young children. IJPC. 2016;20:247-249.
5. Allen LV Jr. Standard operating procedure for performing physical quality assessment of oral and topical liquids. IJPC. 1999;3:146-147.
6. McEvoy GK, ed. AHFS Drug Information 2016. Bethesda, MD: American Society of Health-System Pharmacists; 2016:1918-1932.
7. Physicians’ Desk Reference. 70th ed. Montvale, NJ: PDR Network; 2016:1929-1936.
8. Ora-Plus product information. Allegan, MI: Perrigo; 2018.
9. Ora-Sweet product information. Allegan, MI: Perrigo; 2018.
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