Excipient testing, composition and variability
Excipients are either natural / naturally derived or synthetic / semi-synthetic. In all cases the exipients are obtained through chemical processing of a raw material source that usually has an animal, vegetable or mineral origin.
Besides differences in process technology, conditions and parameters, these raw materials required to produce the excipient are an important source of variability in the composition of excipients. For example, one of the most important components of cellulose ethers is the cellulose raw material itself. No two trees are alike, so there will be inherent batch to batch or inter-batch variability of cellulose raw material.
Why excipient quality testing is very important?
Referring to the sources of variability in excipient composition mentioned above and knowing that the information on a excipient certificate of analysis is limited, it is clear that full monograph testing of excipients cannot exclude underperforming drug products. Excipient variability and the presence of reactive functional groups or reactive excipient-related substances pose a risk.
Excipia offers excipient selection and extra-compendial excipient testing that can reduce this risk or help troubleshoot and optimize drug formulations.
Over the past decades, we have developed unique analytical excipient testing methods and extraction procedures to chemically characterize excipients in detail. We invest in fundamental research into excipients and are still developing new excipient testing methodologies to answer specific customer questions.
With this approach, we can close the gap between the information on the manufacturer’s excipient certificate of analysis and the information that users need to develop a safe and robust pharmaceutical product.
Excipient testing, excipient quality and excipient selection
Excipia provides fast and flexible excipient testing, troubleshooting and excipient quality assessment services to reveal and compare hidden excipient properties like:
The presence of potential reactive impurities
Examples are reducing sugars, aldehydes, peroxides, metals and organic acids.
Reactive impurities in pharmaceutical excipients can cause instability of the drug formulation resulting in decreased product performance, formation of potentially toxic degradation products and loss of potency. Levels of reactive impurities in excipients may vary between batches, grades, and manufacturers.
Reactive functional groups
Like aldehydes, ketones, carboxylic acids, alcohols, amines, esters, etc.
Just like reactive impurities can specific reactive functional groups in pharmaceutical excipients cause drug product instability, leading to decreased product performance, loss in potency, and/or formation of potentially toxic degradants. The levels of reactive functional groups in excipients may be an inherent property of the excipient, such as the aldehydes in monosaccharides, or may be a product of unwanted chemical reactions during processing and purification of the excipient in the manufacturing process or during storage.
Degradation products
Molecular weight distributions (MWD) of polymeric excipients
Polymeric excipients constitute a very large and varied group of substances, including macromolecular compounds of natural origin, e.g., sodium alginate, gelatin, chitosan and cellulose derivatives; synthetic polymers, e.g., polyethylene glycols, poloxamers, polylactides, polyamides, acrylic acid polymers, etc.; and fermentation products, e.g., xanthan gum.
Polymers in pharmaceutical technology are an important class of excipients; therefore, knowing their exact properties is vital. Polymers consist of repeat units (monomers) chemically bonded into long chains. The properties of polymeric materials are dependent on their chemical architecture and overall molecular weight distribution (MWD). Understanding the physical properties of a polymer requires knowledge of the length of the polymer chains.
Degree of substitution (DS) of polymeric excipients
The degree of substitution (DS) of a polymer is the (average) number of substituent groups attached per monomeric unit. The term has been used primarily in cellulose chemistry. Cellulose ethers, or cellulose derivatives, are available in a wide range of products and are widely used as pharmaceutical excipient.
Examples of mostly used cellulose derivatives in the pharmaceutical industry are Methyl cellulose (MC), Ethyl cellulose (EC), Hydroxyethyl cellulose (HEC), Hydroxypropyl cellulose (HPC), Hydroxypropylmethyl cellulose (HPMC), carboxymethyl cellulose (CMC) and sodium carboxymethyl cellulose (NaCMC).
Their properties are related not only to the nature of the substituent but also to the degree of substitution (DS); accurate determination of DS is very important, as DS is the leading measure determining the properties of the product.
Substituent distribution of polymeric excipients
The physical and chemical properties of cellulose derivatives are influenced not only by their molecular weight distribution MWD, type of substituents and degree of substitution DS, but also by the distribution of the substituents within the monomer units and along the molecular backbone.
To obtain information about the distribution of the substituents along the polymer chain, selective degradation by enzymes is used. The applied enzymes need at least two unsubstituted anhydroglucose unit (AGU) to cleave a glycosidic bond, so the approach takes advantage of the steric hindrance of chain-breaking enzymes by the substituents, resulting in a product spectrum different from that obtained with unmodified polymers.
Monomer ratio of polymer excipients
Information about the distribution of the substituents within the monomer units of cellulose derivatives is obtained by complete chemical hydrolysis.
When cellulose is etherified, the hydroxyls are substituted by the etherifying reagent. The average number of hydroxyls substituted per AGU is known as the degree of substitution (DS), a key aspect in characterizing cellulose ethers. Information about the distribution of the substituents within the monomer units of cellulose derivatives is obtained by complete chemical hydrolysis. After hydrolysis all individual monomers are separated, identified and quantified to calculate the ratio.
…….and other featured characteristics and excipient testing on request.
Excipient testing and selection services
With this in-depth knowledge of excipient testing, we can help excipient users to choose the most appropriate excipient manufacturer, select the most suitable excipient quality grade for their finished dosage form, or define custom excipient specifications to control product performance, quality and safety.
In addition, with our small scale pharmaceutical R&D facilities we can perform compatibility studies, produce formulation test batches and develop and optimize formulations.
We can assist manufacturers of excipients in selecting and controlling their raw materials, production processes and optimizing product reliability and consistency.
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