Drug Formulation and The Impact on Analytical Testing
Ryan Kostuck, Analytical Laboratory Supervisor
Vince Bobin, Laboratory Director
Some of the same challenges in creating a formulation are also related to getting accurate and representative results from your Analytical Testing. This article outlines how to avoid some common issues to help ensure your formulation is safe and effective for patients.
- Drugs as free base versus salt forms
- Drugs containing waters of hydration
- Drugs absorbing water
- Drug content uniformity
Salt vs. Free Base
Many pharmaceutical drugs are manufactured as salts such as citrate or hydrochloride. A common example is Fentanyl Citrate where Fentanyl is the free base and Citrate is the salt. When formulating or testing a compounded preparation it is critical to know if the labeled concentration is referring to the free base or the salt form.
In USP the Fentanyl concentration is shown as the free base. The weight of the salt has to be factored into the formulation to get the correct concentration of Fentanyl only. To make 1 mL of 50 mcg/mL Fentanyl you would need to weigh out 78.5 mcg of Fentanyl Citrate.
Molecular weight of Fentanyl Citrate = 528.59
Molecular weight of Fentanyl = 336.48
50 mcg (as Fentanyl) x 528.59/336.48 = 78.5 mcg (as Fentanyl Citrate)
In this example if the formulation had not corrected for the salt and had only contained 50 mcg of Fentanyl Citrate the potency would have only been 64% of the intended concentration. It is extremely important to be clear and specific what the labeled concentration is referring to.
Waters of Hydration
Similar to salt forms, some drugs contain waters of hydration or are called ‘hydrates’. They contain water as part of their chemical structure. An example is Morphine Sulfate Pentahydrate which is both a salt and a hydrate. Water is often ‘corrected for’, similar to the salt form example above, and additional drug weighed out to account for the weight of the water. For some hydrates this may not be correct as USP defines Morphine Sulfate Compounded Injection as the concentration of morphine sulfate pentahydrate which includes the water. If the waters of hydration had been ‘corrected for’ the preparation would have been super potent.
Many drugs contain water that is not part of its chemical structure. That water is often referred to as free water or absorbed water. Some drugs, such as Betamethasone Sodium Phosphate, readily attract and absorb water and are referred to as hygroscopic. Betamethasone Sodium Phosphate in USP has a limit for water at 10.0%. If the vendor certificate of analysis listed the water content as 8.5% this water can be corrected for in the formulation by weighing out additional drug.
However, if a single container was opened and closed to make several batches the drug is likely to absorb additional water. If enough water is absorbed it can cause potency failures since the amount of water being corrected for is now much less than the actual amount of water the Betamethasone Sodium Phosphate contains.
If water absorption is suspected to be the cause of a low potency result the drug can be sent in for water testing. Testing is performed either by Karl Fischer (specific for water) or Loss on Drying (general) depending on the drugs specific USP monograph.
Generally applied to individual dose forms such as tablets and capsules, content uniformity refers to how much drug is contained in each individual unit. Variation in the amount of drug in a capsule, for example, can come from many different steps during the process.
- Blending of the drug with excipients
- Segregation of the drug during capsule fill
- Amount of blend added to the capsule
If potency results on a batch are coming back high or low testing individual dosages from the beginning, middle and end of the process can help to determine if uniformity is the cause. If variability is observed additional testing can be performed at each step, e.g., top, middle, bottom of the blend, to identify where the variability is coming from and fix it.
While often considered for tablets and capsules the same principles can be applied to other dose forms as well. Proper mixing is critical for creams and ointments as well as good formulation development to prevent phase separation during shipping and over time.
Individual vials of suspensions may contain a consistent total volume but can vary in the amount of suspended drug if proper mixing/filling does not occur.
Content Uniformity is important to remember when assessing low or high potency results. It should not be assumed that an incorrect amount of drug was added to the batch. It may be present just not uniformly distributed.
During formulation and analytical testing be specific when referring to the concentration of the drug. Does it refer to the salt form or the free base? Should the amount of drug be corrected for water or not? If a potency failure is obtained during testing first ensure you are comparing ‘apples to apples’ and the drug/amount are correct for your specific formulation. Also consider if the drug may have absorbed water (low potency) or if there may be content uniformity issues (low or high potency).
Analytical testing can help troubleshoot these common formulation problems and establish the quality of the compounded preparation.
Please contact ARL for more information 800-393-1595 or firstname.lastname@example.org.