Activities

Deliverables:Introduction in the report formatDefine buffers systemsDefine drugs to testDefine anlytical tests neededTest

Buffer database in placeMayu work will be limited to the pH's of 5.8 and 6.5FESSIF V2FESSIF V2 Biorelevant (Citrate version)FeSSIF V2 Biorelevant (Phosphate version)FaSSIF V2FaSSIF V2 Biorelevant (Phosphate version)This will include the original buffers, the adjusted Biorelevant buffers and the USP version at the same pHInvestigate buffer species properties:Physico chemical propertiesUV responseTemperature stabilityOxidation potentialOn the point above, do a proper theoretical search about these buffers

Priority propertiesGiven the main objective is to swap the current V2 buffers with new ones that allow us to prepare and sell a concentrate as part of a kit, the following points are to be taken in account:Maintain the salt content the same as the original buffer version. For example, for FaSSIF V2 is 4.01g/l and for our new version it should the 4.01g/l as wellMaintain the buffer capacity the same. E.g. for FaSSIF V2 is 10 mmol/(pH.L)Osmolarity around the same value as the original buffers or isotonicity (280 - 290 mOsm/L). Given this property is 3rd priority we will need the check and evaluate. It will probably be slightly different between versions

Will we be able to prepare and manufacture a concentrate?What is the price of the individual components?Is there any available market forms?

List THE ANLYTICAL TECHNIQUESmake sure we have SOP'sBuffer capacitySurface TensionParticle Size and Polydispersity IndexpH

Solubility studies:We will perform these to assess the effect the different buffers have in a partially water soluble drug at that particular pHThese tests can be done in all the buffers listedEquilibrium solubility from USP literature as a starter. We can adjust this method according to our needs.USP 1236Dissolution studiesWe will run these tests to evaluate the effect the different buffer versions have on a specific product dissolution.Monstly to compare the original V2 versions against the Biorelevant V2 versionsIn house method - 1-step methodUSP 1092

Carbamazepin400mg maximum dose100% solubility in 900ml dissolution vessel: 0.444 mg/mlWater solubility 0.152 mg/mLBCS class 2logP 2.1Montelukast10 mg maximum dose100% solubility in 900ml dissolution vessel: 0.011 mg/mlWater solubility pH dependantBCS class 2logP 7.9Ibuprofen800 mg maximum dose100% solubility in 900ml dissolution vessel: 0.888 mg/mlWater solubility pH dependatBCS class 2logP 3.5Nebivolol5 mg maximum dose100% solubility in 900ml dissolution vessel: mg/mlWater solubilityBCS class 2logPDiclofenac sodium

DeliverablesWhat are the buffer formulations we are going to use?Do the media made up with these new buffers behave the same as the media with the old buffers?Can we detect any differences on drug solubilities when using the media made up with the different buffers?Can we detect any differences on drug dissolution profiles when using the media made up with the different buffers?

Deliverables:Update the buffer database with the accurate formulationsDevelop SOP's for the preparation of the buffersWrite up the results in the Project report

Starting with the buffer database formulations prepare the buffers and test the relevant properties

Investigate the temperature effect over the pH valueEvaluate temperature at 22C and 37CAim for the perfect pH at 37C

Using the spectophotometer perform a UV spectrum measurementDefine the UV cutoff of each bufferQuickly investigate the degradation under increased temperature and the effect it has on the UV absortion of the different buffersDo an accelarated stability study to "kill" maleate b uffer

Compatibility with common solvetnsAcetonitrileMethanolTHFCheck for precipitation issuesAt which ratio do the salts from the buffers start to precipitate?

Assess if there is any issue when mixing the buffer with the appropriate biorelevant media

Deliverables:Define media shelf life time with the new buffersDevelop a stand alone document that compares the properties of the media when using original V2 buffers versus biorelevant V2 buffersProject write up in the project report

Investigate the Lukas paperTime: 48H stored + 2h usage as a maximum storage and use time

Consider the following propertiespHSTBCPCSUVEvaluate the condition of the equipment needed for the experiments

Deliverables:Show evidence in the form of a plot of the influnce of the different buffers on drug solubilitiesStandalone document / white paperProject write up in the Project report

Carbamazepin400mg maximum dose100% solubility in 900ml dissolution vessel: 0.444 mg/mlWater solubility 0.152 mg/mL (tbc)BCS class 2logP 2.1pka - neutralUV max 285nmIbuprofen800 mg maximum dose100% solubility in 900ml dissolution vessel: 0.888 mg/mlWater solubility pH dependentBCS class 2logP 3.5pka 4.85UV max 264nmDiclofenac sodium100 mg maximum dose100% solubility in 900ml dissolution vessel: 0.111 mg/mlWater solubility pH dependentBCS class 2logP 4.98pka 4UV max 280nm

Decide which solubility method we want to useProper equilibriuym vs adapted method?Decide the duration of the studyTemperature of the study, 22C vs 37CDecide the analytical method to useUV possiblePay attention to the pH changes over the solubility study timeConsider a miniprobe

Analytical method

Deliverables:Show evidence in the form of a plot of the influnce of the different buffers on the dissolutions of the drug product formswhite paperDraft document of the 1-Step dissolution protocol for the V2's kits

Make sure we already have a definitive 1 step method in a protocol formdecide the duration of the studyDecide the analytical method to useDissolution of fresh media vs aged media?

Deliverables:Updated database with all the data