foreign [Music] welcome to this on-demand webinar my name is Shanta Julie I am Global product manager responsible for quaternary ammonium compounds at novonotis pharmatic today I would like to discuss the importance of choosing an antimicrobial ingredient for pharmaceutical formulations and I will be focusing on benzylconium chloride when choosing an antimicrobial ingredient for your formulation you will probably already know if it's for use as an active ingredient or as an excipient as a preservative if it is as an active ingredient you would probably have to follow local GMP guidelines and Source a GMP quality ingredient you would be needing several pieces of documentation such as probably a drug Master file statements certificates questionnaires and so on and and of course you would be looking for compendial compliance if available for example to the European the American the Japanese from acupay and preferably also compliance both to pharmaceutical monographs and general notices and general chapters it is very similar for excipients however it is not all countries that require that you follow GMP guidelines for excipients but you can at least get some inspiration from the iPic guidelines or the exit pack guidelines it is preferable based on a risk-based assessment to Source a GMP manufactured excipient again if available or at least in the quality that is acceptable for pharmaceutical use and then you would probably be looking for a broad range active ingredient that is also simple robust and preferably cost effective then there are also many other aspects that you can look at and if we look for example first of all at the ingredient itself of course you want it to be efficacious you will have to evaluate if you are looking for a broad spectrum active ingredient or if you want to focus on one specific microorganism and that would be most relevant for for use as an API for example then you also want it to be safe and you want it to be in a quality compliance for pharmaceutical use then you can look at your supplier you want to look at the supply chain safety for example you want to ensure that you have an excellent communication with your supplier both under the qualification period but also after you have purchased the product ensure that you get information on changes in documentation or processes in changes affecting the quality of the product and of course you want to be able to audit your supplier when looking at your Finnish drug formulation you would consider the therapeutic area you would consider the root of administration and also the type of delivery system if it's for example for multi-dose use or single dose then why would you choose benzocrine chloride as an antimicrobial for your pharmaceutical formulation well benzylconium chloride has been around for a while it is a very well known molecule already back in the 1940s it was reported for use as a preservative in ophthalmic Solutions it is very well documented its effect antimicrobial effect is very well documented in in several scientific papers it is a very stable molecule it is very resistant to several temperature and humidity conditions and we have tested of course the product according to ichq1 stability guidelines and also under all available climatic conditions and the molecule is proving to be very very stable it is also effective throughout a very wide PH range so we are talking about 4 to 10 or even 11 in terms of PH range and I will come back to a pH later on during this webinar then also the molecule is a surfactant it is a cationic surfactant so it is positively charged and it is attracted to surfaces which gives it several nice properties in terms of if you want to prepare a topical formulation it can help it stick to the skin for example or the mucosa if we look at the benzoconium chloride molecule which is quite a simple molecule you have a chloride ion you have a benzyl ring and you have the nitrogen atom with methyl groups and also along alkyl chain oily alkyl chain attached to it standard benzoconium chloride for Pharma used normally will have a mix of 12 and 14 carbons in the alkyl chain link again the molecule molecule is positively charged and this charge is not affected by environmental conditions also another interesting property of the molecule is is it it's that it is that it has a hydrophilic and an hydrophobic part which can be used for example in formulations oil and water formulations that can help keep an Emulsion together so the mode of action of benzylconium chloride is very much related to the molecular structure so the molecule is positively charged and therefore it is attracted to negatively charged surfaces and it can be the skin mucosa hair or also microbial membranes so it attaches very strongly to microbial membranes and then the oily alkyl chain length which has a structure that resembles the lipid structure within the microbial membrane will penetrate it and create openings and and destabilize the structure of the microbial membrane and then this will in the end cause death of the microorganism there are also other mechanisms involved but this is the main mechanism behind the effect of enzyclonal chloride in killing microorganisms in terms of antimicrobial efficacy again the antimicrobial efficacy of benzoconium chloride is very well documented in scientific papers nevertheless we wanted to have our own tests performed to verify the efficacy of our own product therefore we commissioned the Danish serum Institute to test benzirconium chloride against gram-positive gram-negative bacteria and yeast so we chose a range of microorganisms that are part of standard pharmaceutical testing for antimicrobial efficacy so we included for example candida albicans staphylococcus aureus also including a multi-resistant strain and pseudomonas IRA genosa so here benzylconium chloride was tested against ethanol and against a positive control with an antibiotic and what we could observe in terms of minimal inhibitory concentrations was that extremely low concentrations of benzocrine chloride were necessary to control these microorganisms also compared with ethanol were much higher concentrations were required slightly higher concentrations can be required to control pseudomonas aerogeneosa and this is quite well known and well documented you can choose to either use higher concentrations of benzirconium chloride or you can choose to use benzyclomine chloride in combination with chelating agents for example EDTA that would act synergistically and increase the effect of benzylconium chloride against macro organisms chloride also effective against viruses as mentioned yes against enveloped viruses so this is because of the mode of action of benzylcoin chloride it requires a membrane to be effective so it would not be effective against a non-enveloped viruses examples of enveloped viruses can be adenoviruses herpes HIV sarskovi hepatitis A and B for example to name a few so benzoconium chloride is effective indeed against these microorganisms we have performed a very comprehensive literature review to support this and we have also published a white paper on this topic that we can make available for you in this literature review we also observed that concentrations of bkc of 0.5 percent or even less were sufficient to control these macro organisms an interesting fact to mention as well is that benzylconium chloride is a recognized efficient antimicrobial effective against covid virus and this is recognized by several National agencies such as the usfda the EPA or the Canadian Health authorities so this is very relevant for topical applications such such as antiseptic Solutions and creams but benzylcoin chloride is also used in several other applications yes benzoconium chloride is used in a very wide range range of applications very often as a preservative as an excipient in ophthalmic or nasal Solutions there it is very well known as a preservative as an API you would often find it in creams against psoriasis herpes acne eczema you would also find it in in nappy rash creams you find it in a wound disinfection solutions for clinical disinfection pre-operative surgery and so on you also find it in oral products such as throat lozenges also products to treat cold sores gum problems gum pain and so on benzylconium chloride is also a spermicide so you can also find it as an API in spermicidal gels or creams and there it would have a dual effect as well having an effect against HIV virus for example where it is would also have an antimicrobial effect and this goes for both human and Veterinary drugs so the pH of the final pharmaceutical formulation is important because pH can affect the growth of microorganisms it can also affect the interaction of a preservative with cell wall components and in the end also the inhibitory effect of the preservative microorganisms grow best at physiological pH between six and eight than if it is possible for you to prepare formulation outside this PH range this might help control microbial growth however however it would not replace the use of a preservative in the formulation benzylconium chloride is effective at a very wide PH range as mentioned between 4 and 10. so if you wish to if your formulation has a pH outside the PH range of six to eight you still want a preservative such as pkc to be effective Within These pH ranges then additionally benzocrine chloride is even more effective at higher pH because this affects the cell wall components and make microbial cell walls even more negatively charged which helps binding of the benzoconium chloride to the membranes therefore if your formulation is at very high pH you might consider using a lower concentration of benzoconium chloride as a preservative so the topics were we discussed today were important aspects in choosing an antimicrobial ingredient for Pharmaceutical formulations we took a closer look at benzylconium chloride as an antimicrobial ingredient the molecule and its mode of action and we also touched based on ph and its importance in Pharmaceutical formulations I hope you enjoyed these contents we thank you very much for watching and please do contact us if you have questions foreign [Music]