Extemporaneous Formulation

Introduction

Despite the shifting of pharmacy focus to pharmaceutical care, the practice of compounding pharmaceutical formulations remains an essential skill for pharmacists. Being a drug expert, we are expected to know them all.

  • In the 1920s, hiring a hospital pharmacist in the United States was necessary for controlling the inventory and manufacturing alcohol-containing preparations, which were expensive to obtain commercially.
  • Nowadays, it is recommended to use commercially available products whenever possible. If no suitable commercial product exists and no therapeutic alternative, then extemporaneous preparations should be made based on evidence-based references.
  • When no stability information is available, pharmacist may dispense oral tablet or capsule and direct the caregiver to freshly prepare just prior to administration.

Handling Prescriptions with Extemporaneous Preparation Medicines in the Pharmacy



Extemporaneous Formulation References

There are many references available for extemporaneous formulation, including



Malaysia

Ministry of Health Malaysia has made efforts to search for substantiated references in producing the Extemporaneous Formulation, 2015.

  • It standardizes Malaysia MOH facilities' extemporaneous formulation, hence preventing medicine dosing errors occurring due to mix-ups if different strengths are prepared by different pharmacies.

Extemporaneous Formulation

Key Reminders

  • When a commercial preparation is available, consider it first.
  • As highlighted in policy, stability stated in this manual is applicable to shelf storage in the pharmacy without opening. Once opened, the stability of the preparation should be no longer than 30 days. Maximum quantity of the extemporaneous preparations to be dispensed should not exceed 1 month. Many stability studies do not assess the effect of in-use conditions on physical, chemical and microbiological stability.
  • Pharmacy personnel are reminded not to empirically change flavourings or suspending agents because they can affect the pH and stability of the product and result in an unstable product.
  • Product should be labelled clearly and stored as recommended within the formula.
  • For solution or suspension products, emphasise on the importance of thorough shaking before use.

There is a formula that I would like to raise the issue on, that is caffeine citrate solution 10 mg/ml.

Caffeine Citrate 10 mg/ml Solution

Most hospitals in Malaysia are unable to obtain the raw material caffeine citrate anhydrous BP stated. On the other hand, we bought caffeine anhydrous powder instead via import permit. In conversion, 2 mg caffeine citrate = 1 mg caffeine anhydrous. By using caffeine anhydrous powder 1g for 100 ml, the final preparation is actually caffeine anhydrous 10 mg/ml, NOT caffeine citrate 10 mg/ml effectively. This will in turn affects the dosing that we are going to use.

The extemporaneous formula that I personally suggested to use is stated in Micromedex NeoFax:

  • Alternatively, an oral solution may be prepared by dissolving 2.5 g of caffeine anhydrous powder in 250 ml of water, yielding a final concentration of 10 mg/ml caffeine base. Solution is stable for 4 weeks refrigerated. Crystals form when stored at low temperature but dissolve at room temperature without loss of potency. Do not freeze.
  • In this case, it is important to shake the suspension very well until now visible powder (including before each use) and to use caffeine anhydrous based dosing.

Apart from this reference, another equally important reference in MOH facilities would certainly be X-Temp Master Formulation Sheets.



Vehicle in Extemporaneous Formulation

Flipping through Extemporaneous Formulation, 2015, you may come across a total of 4 common vehicles, namely:

Simple Syrup

  • Is a sucrose solution, which has a sweet taste.
  • Technically, one or more antimicrobial preservatives may be added.
Ora-Sweet: Ora-Plus (1:1)
  • Ora-Sweet is the modern version of simple syrup flavoured with a citrus-berry blend for a highly palatable taste. It may be used alone or in combination with other agents. It will retain its flavouring properties when diluted up to 50% with water or suspending agents.
  • Ora-Plus is a unique suspending vehicle retains its suspending properties when diluted up to 50% with water, flavouring agents, syrups or alcohol.
  • Ora-Sweet and Ora-Plus can be combined in a 50:50 ratio to produce a pleasant tasting elegant suspension.
Ora-Blend

  • Ora-Blend is a flavoured oral suspending vehicle used to simplify the process involved in the extemporaneous compounding of oral suspensions. It combines the suspending properties of Ora-Plus with the flavouring agents of Ora-Sweet. Medicated powder can be incorporated into Ora-Blend to form elegant, uniform and physically stable suspensions.
Ora Sweet SF or Ora Blend SF
  • It is generally considered acceptable to substitute sugar-containing Ora products with sugar-free Ora products.
  • However, it is not advisable to use sugar-containing Ora products if a study has been performed using sugar-free products. This is because sugar can cause chemical stability problems or discolouration with some drugs (e.g. the Maillard reaction).
  • Nonetheless, using Ora SF products instead of Ora Sweet may cause physical instability with some specific formulations.
X-Temp Oral Suspension System
  • Orange flavoured, sweetened, sugar-free vehicle.
  • Contains specialized suspending system formulated to assist in extemporaneous preparation of oral liquid, non-soluble (suspended), aqueous dosage forms.
  • Contains suitable preservatives: Methyl hydroxybenzoate, propyl hydroxybenzoate, potassium sorbate.
  • The X-temp Master Formulation Sheets lists many extemporaneous formulations that based on studies using Ora-Sweet/Ora-Plus 1:1 combination. Few local stability studies that have been carried out for X-Temp Oral Suspension include spironolactone 1.25 mg/ml and 5 mg/ml, folic acid 1 mg/ml, captopril 1.25 mg/ml, morphine 10 mg/5 ml, phenobarbitone 10 mg/ml, isoniazid 10 mg/ml, chloral hydrate 40 mg/ml and hydrochlorothiazide 5 mg/ml.

NOTE: X-Temp Oral Suspension and Ora-Blend SF (SF stands for sugar free) are not exactly the same. 2 major differences include:

  • Ora-Blend SF has simethicone as an antifoaming agent (not present in X-Temp Oral Suspension).
  • Although both Ora-Blend SF and X-Temp Oral Suspension are buffered to a pH of about 4.2, the osmolarity of Ora-Blend SF is slightly higher (1073 mOsm/kg vs 950 mOsm/kg).

X-temp Alka Powder for Oral Suspension System

  • Composition: Calcium carbonate, potassium carbonate, sodium alginate, sucralose, methyl paraben, propylparaben.
  • Sugar-free, alcohol-free and colourant free.
  • pH buffered for enhanced compatibility for alkaline medications (pH >7)
    • Omeprazole 2 mg/ml: 90 days at 2-8°C
    • Pantoprazole 2 mg/ml: 90 days at 2-8°C
    • Esomeprazole 4 mg/ml: 90 days at 2-8°C
  • Suitable for pediatric and geriatric preparations.

X-Temp Alka

NOTE: Based on practical experience, omeprazole capsules do not readily dissolve in X-Temp Alka, even with vigorous shaking.



Preservatives in Extemporaneous Vehicles

Another often overlooked consideration is the use of preservatives in extemporaneous compounding vehicles.

  • According to the KIDs List (Key Potentially Inappropriate Drugs in Pediatrics), the use of methylparaben and propylparaben (found in commercial vehicles like X-Temp and X-Temp Alka) should be approached with extreme caution in infants younger than two months due to the risk of kernicterus.
  • Furthermore, the European Medicines Agency (EMA) advises against the use of propylparaben-containing oral medicines in neonates and infants under two years of age. This recommendation stems from concerns regarding potential endocrine disruption and the immaturity of the metabolic pathways required to clear the preservative.
  • When compounding for neonates, freshly prepared, preservative-free solutions are often the safest and preferred alternative, despite the clinical trade-off of a significantly shorter in-use shelf life.

For commercial products, formulating medications as dry powders for reconstitution (commonly seen with antibiotic oral suspensions) is a highly effective strategy to mitigate stability and contamination risks.

  • This approach achieves a much longer baseline shelf life, as bacteria and fungi cannot proliferate in a dry powder devoid of an aqueous environment.



Considerations for Alcohol as a Solvent

In pharmaceutical preparations, alcohol is an essential and commonly used solvent.

  • In external preparations, it exhibits bacteriostatic properties at low concentrations and bactericidal activity at higher concentrations.
  • Coupled with its high volatility (rapid evaporation rate), it is frequently used in the production of lotions for external application.

However, the use of alcohol in internal preparations is generally limited for several reasons:

If ethanol 96% is required for an internal preparation, it is important to realize that only undenatured ethanol 96% is suitable for internal use due to the toxicity of methanol (methyl alcohol) with denatured ethanol.

  • To illustrate, Industrial Methylated Spirits (IMS) is an ethanol that has been "denatured" by the addition of wood naphtha, rendering its unfit for internal use.
  • Other common denaturants include isopropyl alcohol, acetone and methyl ethyl ketone, all of which are harmful if ingested.
  • In short, denatured ethanol has been intentionally made poisonous, foul-smelling or bad-tasting to prevent its use in alcoholic beverages. This process exempts it from the heavy taxes on drinkable alcohol.

Another special consideration in pediatric use is the risk of ethanol causing CNS depression and hypoglycemia. Strict limits are advised for ethanol content in pediatric formulations:

  • Caution in younger than 6 years old: maximum 0.5% v/v ethanol with clinician supervision.
  • Caution in younger than 12 years old: maximum of 5% v/v ethanol with clinician supervision.

Furthermore, due to the risk of fatal gasping syndrome, exposures exceeding 99 mg/kg/day of benzyl alcohol, sodium benzoate, and benzoic acid should be strictly avoided in neonates (younger than 1 month old).

  • The only exception to this rule is the use of sodium phenylacetate/sodium benzoate for the treatment of urea cycle disorders.
  • Because of these severe risks, manufacturers of many parenteral medications (e.g., Vitamin K injections) advise against their use in children under two years of age if they contain benzyl alcohol.



Summary

Often, the stability assigned to an extemporaneous formulation refers to its chemical and physical stability within a properly sealed storage environment, rather than the real-world conditions where a patient opens and pours the preparation daily.

  • In reality, the actual in-use shelf life can be significantly shorter due to repeated exposure to oxygen (causing oxidation), moisture (causing hydrolysis), and microbial contamination.



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