1.You can delay dissolution in stomach if you prepare harder tablets/pellets

2.By Enteric coating (granules and compressed to tablets/pills)

3. Addition of higher DCP in tablets or pellets may slightly delay break down in stomach

Thank you on your response. How about surviving higher pH? Say intestinal pH is roughly 7-8, will the enteric coating helps?

Sorry again, what you meant by DCP?

1.Yes if you select suitable coating material

2.DCP= Di-calcium phosphate

Ok thank you very much Dr. Chakravarthy.

So what coating materials you suggest?

hi firas! is the ester a simple one like an alkyl ester ( like methyl, propyl, pentyl etc etc.) or it contains complicated groups on both the sides of the ester linkage ( for example the ester linkage in taxol). Pls let me know this---then maybe i can help.

1.Cellulose acetate phthalate as an enteric coating material

onlinelibrary.wiley.com/doi/10.1002/jps.3030401014/pdfby CJ Malm - 1951 - Cited by 16 - Related articles

enteric coating material. This ester and its salts have been disclosed in patents by Malm and Waring (5) and have been more fully de- scribed by Malm and ...

2.Eastman™ C-A-P Cellulose Ester NF (Powder)

www.eastman.com/Products/Pages/ProductHome.aspx?Product...C-A-P enteric coating material withstands prolonged contact with acidic gastric fluids, but it dissolves readily in the mildly acidic to neutral environment of the ...

2012 Top Esters Companies in Pharma

www.jazdlifesciences.com/pharmatech/leaf/.../Esters.htm - United StatesEastman C-A-P Cellulose Ester NF (Pellets) Eastman C-A-P enteric coating material is a pH-sensitive cellulose derivative designed for coating pharmaceutical ...

You can also micoencapsulate your active ingredient........

Hello Siddharth, sorry for late reply.

Yes my ester group is going to be between two complicated molecules. I have to perform an esterification reaction in SN38 on the C10 position and i want to add a peptide chain along with some PEG group. I want that prodrug to go lymph system, hence I want it to survive the acidity of the stomach and the basicity of the GIT. Still not quiet sure whether to make bigger molecules or whether to use enteric coatings.

And Marina, how and what is the best way to microencapsulate the active ingredients?

Thank you for the help.

Firas

Hi Firas!

If you want the drug to go to the lymph system try IV or IM rather than oral intake methods! But if you have no choice but to give it orally then you can use any of the methods given above by many people! Coatings will help reduce the damage your drug takes and even gelatin capsules can be used! And if this prodrug is actually a medical treatment then you may consider giving this prodrug in conjugation with a H2-blocker or some pepsin/Hcl blocker like ranitidine! and if u want your prodrug to survive the basicity of the GIT then consumption of water with the prodrug ingestion is useful and even your encapsulation will help to avoid basicity!

And if u want a chemical solution to this problem then i would like you to post an image of the ester bond with some few groups on the side ( don't disclose your research by giving the full structure of the prodrug... just give me a background of the two groups present at the two ends of the ester bond). I cant do much just by knowing that it is a ester bond! If u give me the structure of the nearby chemical structures then maybe I can formulate a chemical protection and later de-protection mechanism!

Thanks Firas! Cya Soon!

Sid

Hello Siddharth, this is the ester group that i am trying to protect. I have to formulate an oral route for this one. its just the ester sketch but its actually a quiet big structure beyond the benzene ring.

Is there a way of drawing neat structures in here?

well firas! I would like to apologize to you on this one! u gave me a polymer tail on one end while and benzene on the other! the thing is the polymer tail cannot be altered cause bringing about a change in the polymer would means ineefective delivery of the drug! however on the other side of the ester bond u gave me a benzene! and benzene is a very stable group and as far as my knowledge goes.....no reagant would react with benzene without actually distroying the ester bond! so i am sorry again for the delay..............but pls give me some nearby functional groups also! because i can only think of reaction with a functional group to protect your ester rather than doing anything on thr hydrocarbon skeleton! Pls give a little more background of the end containing the benzene group...............

If u feel that your research is at an risk if u reaveal more of the structure....then i am soorry...I am of no further assistance to you! Thanks!

Sid

Hello Sid,

I can give up to this point in the structure. Thats ok if there's no way in protecting the ester group. I might refer to enteric coating methods if that would be the best idea to do so.

Thank you

Firas

Hi Firas!

I think that this comment should end the discussion! Well I am with enteric coatings and micro-capsulation (gelatinous or other). This is because these methods are easy to perform and quite cheap as well. There are really not much hassles in this kind for methods but you asked for a chemical method to protect your drug... and I being a chemical guy... am bound to do so!

The biggest hurdle in chemical protection of drugs is that they need to be de-protected later on. So even if I would give you a protecting compound then u will have to de-protect your prodrug later on... which would mean putting some other compound into the lymph to cause de-protection. Since we know our bodies are not chemical flasks... so i wouldn't recommend that.

Go for enteric coatings or micro-capsulation! they are the logical choice! But I am a chemist and so I can't disappoint you! If you still need a chemical method although enteric coatings would be better... then this is the the method i would suggest...

Create a molecule which would protect your ester bond selectively and would not react with any other part of the prodrug! Then after protecting the drug... ingest the drug and it will pass away easily through the GIT and into the Crypts of Lieberkuhn and hence into the lymphatic system... you would then want a biological enzyme(s) to break away the protecting molecule and hence freeing your drug into the lymph! But you would want the protecting compound to be non toxic and having a short half-life... so that it does not accumulate in the body

So I have designed a molecule for this purpose! The mechanism of protection, 3-Dimentional view of the protected prodrug and the synthesis of the protecting compound are shown below!

For de-protection of the prodrug... The enzymes like Mono-oxygenases will convert the isopropylidine part of the protecting compound into a ketone counterpart and hence de-protect the prodrug from the oxygen end and then the Isothiocyanide molecules present in the lymphatic system would de-protect the prodrug from the Pyridine's Nitrogen end... hence completely de-protecting the prodrug! Infact the deprotection could also be done by esterases present in the lymphatic and circulatory system!

The real concern however is about the toxicity of the protecting compound. I have no idea whether the protecting agent is toxic or not! Although I think it will have a short half-life due to the highly polar flourine atoms!

This is all I could do for you! This is all a crazy 1st year chemistry student can do for you! Please tell me whether I was of some assistance or some confusion! Thank you!

Sid

Mechanism of Protection

3-dimensional view of the protected drug

Synthesis of the protection compound

Thank you SId, I will try this method, you are of a great help :)

Firas

Hi Firas, I'm glad you thought so! Take care an best of luck for your research!

Thank you!

Sid

I am sorry Guys....the protection group you showed does not exist so far. Moreover acid chloride doesnt undergo wittig reaction, difficult to handle that. There are many drugs which contain esters and lactones in their structure, just give it a try with your compound for the testing. dont waste time to synthesize all these protection groups. there is no chemical protecting group to survive an ester. best of luck.

1. As Sunil says it is difficult to protect esters thru tough acid medium of the stomach.

2. Does it harm if the ester is hydrolyzed to acid? Does it make the drug insoluble? Does it alter its biological activity much? Pl think. If it is not coming in the way let it be hydrolyzed!

Ah! Sorry! I just thought of helping!

thank you Bapuji and Sumreen for the extra information :)

I am trying to get the drug into the lymph system. As I don't want the drug to be metabolised before it reaches the target, i thought of creating a prodrug by forming an ester bond where the hydroxyl is present. The prodrug has to be lipophillic and with Log value of above 5. On the second sketch above i have circled the oxygen in red, this was a hydroxyl and now its an ester bond. On the other side of this structure is a lactone group (not included in structure above), i want the lactone group to be stable as i don't want it to open and change to a carboxyl form. As the ester bond breaks down under acidic conditions, i am trying to protect it so it can pass through acidic condition and reaching the lymph system, where then the ester bond can then breaks down and leaving the active drug to go to target.

If you want to protect your drug from acidic conditions in stomach, there are drug forms dissolving in intestine. You should consult with someone interested in technology of drug forms.

I am ignorant of this problem but very curious to learn the solution!

If we protect any molecule by physical / enzymatic masking or chemical manipulation, I think its properties would not be the same! You are not studying what you really want to!

It is worth struggling!

Why don't you try the alcohol as a precursor for the acid? Take a look at Losartan's P450 mediated activation(oxidation) to the ultimate drug. Works well on benzylalcohols. Several prodrugs were developed to protect acids: Ethoxy-CH(CH3)O2C-R was used by Boehringer. Start simple: use isopropyl (it us not a good substrate for most lipases/esterase, but has better stability against pH in the gut than tBuO-Esters). Cholesterolesters were used to pass the Blood brain barrier.

Similar approach: Vitamin C ester

I think Mark and Vladimir are right , the best solution would be check if the compound actually breakdowns in that pH range and analyse, as far as lookign for stable protecting group the strong protecting group you choose harder it would be to get rid off, in the later stager, which is another problem again.

alternatively you can think of less easily hydrolyzed groups as in the case of anesthetic procaine (obtained by molecular modification of coacine) where in they repalced the ester group with amide group forming much effective lidocaine.

Having large groups such as methyl on one or both of the esterifying moieties to be next to the ester bond may provide sufficient steric hindrance to slow the ester hydrolysis.

Any info on protecting groups: greene's protective groups in organic synthesis is the book you should read. Really good comprehensive book.

The solution exist yes and among others I see a bulk (bulky) substituent to avoid an approaching nucleophile (hydroxide) and also avoid the lipoficicidade protonation in acidic thus preventing the formation of water as a leaving group, the problem is that the increase in chain carbonic may decrease the water solubility

actually in some cases acetoyl acetate ester of alcohols works on delivery system. I think you might get more details from literature about this. i think you should consider what Mark and Schmidt say

Hi everybody,

Setya and Vladimir were the best answer, quite right. I am specialist in drug delivery systems, as Cyclodextrins, Polymers and Lipossome. If you know that group is the pharcophoric part of the drug to the target you need to do a QSAR / 3D QSAR about the exactly molecule and discovery what the best host molecule to protect the guest in that case the pharmacology ativity drug (whatever the molecule with the esther group) Along past years i and mine colobarators had studies with theory and experimental investigations about this kind of problems with Local anesthetics, AZT and HIV drugs, Iron II Lactate, etc. In the case, e.g., of Iron II Cyclodextrins block the oxidation to Iron II i believe that is the way. If worldlike contact me to do this work. Look at my perfil some of these works. Good luck! 8- )

Sumreen Javed,

Very good article, inspirational.

Id like the molecules as PCTA, RibCys, CySSG and Sulfasalazine toutes PRO DRUGS I would to test some host molecules interactions with these structures.

Best Regards

8- )