Soft and Hard Gel Capsules - Sample Prep Technique

[Blazer]

Hello all,

After spending the last five years performing analytical method development on creams and ointments for a dermatological company, I now find myself working for a different company doing similar analytical development work, but on solid dosage forms, particularly soft gel (and eventually I suppose) hard gel capsules.

These dosage forms are completely new to me, so I was hoping that some of the more experienced members of this forum might shed some light on the techniques they use to sample these capsules. Since I just started my new position, I've been reading the internal documentation and talking with other people here. It seems the standard procedure they talk follow includes "piercing the shell and squeezing the contents into a vol flask" and then "cutting the capsule in half and adding these halves into the vol flask". Diluent is then added, followed by shaking or sonication to complete the extraction. I have tried this and it is not easy, with much of the liquid fill material ending up on the tools used to grip, pierce, and cut the capsules. This of course leads me to believe that there could be a recovery issue eventually with this technique.

So my questions are: Is this the standard technique for soft gel capsules? Are there other alternatives that might be easier?

Again, I come from working with creams/ointments so capsules are new to me completely. I'm not looking to re-invent the wheel, so hopefully someone can offer some suggestions.

Thanks,

-Blazer

[Mark Tracy]

I've never done it either, but your question is too interesting to resist. I would not use volumetric flasks at all. I would use screw-cap Erlenmeyers. Next I would get some long, heavy tweezers. Then one of those crocodile scissors that surgeons use for working in confined spaces.

Put the capsule into the flask, and dissect it with the tools. Leave the tools in the flask. Weigh the diluent into the flask. Sonicate and stir to complete the extraction. Pull the tools out and cap the flask. You will need to measure the density of the diluent to convert weight to volume; easily done with a volumetric flask or pycnometer.

[Bruce Hamilton]

Way back in the 1970s, we used to sample soft and hard gel capsules by weight. Simply squeezing 20 soft gel into a preweighed container for the average, and individual preweighed capsules and containers for the consistency assays.

Same procedure for hard gel, except they could often be pulled apart and the solid contents emptied. We then used the separate quality data available for the batch to provide mass of formulation added to the capsules to calculate capsule content of analytes.

Seemed acceptable then, but we were mainly making things like vitamins and aphrodisiac products in such capsules.

Bruce Hamilton

[Dan]

Blazer,

First let me apologize for a long response, but I do want to provide a complete answer.

You have pointed out one of the strange quirks for sample preparation in the pharmaceutical industry: the use of volumetric flasks for the sample preparation of dosage forms. Soft gelatin capsules are one example of a dosage form for which the sample preparation is not easily done using a volumetric flask.

Volumetric flasks are designed for making volumetric solutions. It sounds like a simple concept but there are an amazing number of sample preparations for dosage forms that I have seen that inappropriately use volumetric flasks. The necks of the flasks are often too small to allow the tablet (or capsule, or cream or ointment) to fit. So the method calls for the tablet to be broken first and then transfer ALL pieces into the flask. Try doing that for 10 or 20 tablets without losing any pieces Then you have the issue of undissolved dosage form components that give volume errors. Dilute to volume but you don't get that volume when the shells of 10 soft gelatin capsules are in the flask. At one place, we couldn't change the sample preparation so we added a volume correction factor as the volume of the undissolved shells of 10 soft gelatin capsules contributed to several milliliters in a 100 mL flask. The volume errors are usual not significant for tablets or hard gelatin capsules, but they can be significant for creams, ointments and soft gelatin capsules.

In your case, you need to come up with a way to cut the capsules and get the shells and the entire contents into the flask. Not easy to do without some mechanical means.

Mark has a great suggestion, change to a different flask/container. Use something with a wide opening to allow for easy transfer of the cut shells and contents without loss. Maybe use a rinse with the sample solvent to ensure complete collection of capsule contents into the flask. Or, as Mark also suggested, cut the soft gelatin capsules while they are in the flask.

Remember that if you rinse your cutting device, then you will need to know the total volume of rinse solution (and that of any other added solvent), because you will not be "diluting to volume".

After you get your capsules cut into the flask/container, cap it and then proceed with shaking/heating/sonication and filtering as needed.

You may not see many hard gelatin capsules any more as they are being phased out due to product tampering concerns and lack of a clean source of gelatin material (the gelatins were previously coming mostly from animal sources and that is not allowed after the crisis of the mad cow disease).

If you do need to analyze hard gelatin capsules, then you would proceed similar to a tablet sample preparation. You can use the whole capsule, the hard gelatin shells usually break apart easily in the typical sample solvents. Also, you can open up the hard gelatin capsule very easily and drop the contents (and shells) into a flask.

Hope this helps.
Regards,
Dan

[HW Mueller]

Seems to me that analysts doing gravimetric analyses have long since solved these problems? Probably a simplified Version of Mark´s suggestion would be adequate: Get your analyte out and dissolved somehow, transfer it via a filter to a volumetric, fill to the mark.

[kkassan]

Back in the 80's, I worked for a company that made soft gels. Freshly made, they are quite soft and pliable, but they are dried prior to shipping and become extremely hard and impossible to cut with scissors. As they age, they can absorb (adsorb?) moisture and soften a bit, so the sample prep techniques varied.

A usual method was to cut with scissors, if possible, into a graduated cyclinder with a clear glass funnel on top. The contents of each capsule was squeezed into the cylinder, then the shell cut into pieces and also dropped in. The sample diluent was put into a squeeze bottle and used to rinse the scissors and funnel directly into the cyclinder. The volume of a shell was determined mathmatically and the appropriate amount subtracted from the total. At least 10 caps were always used.

For really hard capsules, there was a custom cutting tool (stainless steel), sorta hard to describe, think of an inverted T. The bottom was two pieces each with a semicircular cut out. A single edge razor blade was placed between in the cut out area and the two pieces screwed together. The stem was attached to one of the bottom pieces and was a hollow post with a plunger inside. The capsule was placed on top of the razor blade and the plunger pushed, cutting the capsule in half and then the 2 halves fell into the cyclinder. It may still be is use, you might want to check with some capsule manufacturing companies.

The shells were usually included because some stability study indicated some drugs (more polar?) could migrate from the oil based fill. I'm sorry, I don't remember the specifics, it's been awhile.

Some capsules were heated to dissolved the shells (usually added polysorbate 80), typically vitamins, which I think is now in the USP. Of course, good filtering was required prior to analysis.

My first post, hope I did it properly!

[HW Mueller]

Well, Kathy, you got me out of my paranoia stupor..... I now seem to have done an about face and deny myself the fact that all this pharmaceutical stuff is for swallowing, including capsules. This means of course that they dissolve in aqueous media. So why not just throw the capsules into an aqueous solution and wait (or better use AA´s stirrer). Workup would probably be via SPE or ultrafiltration?

One thing though: I wonder about a squeeze bottle in an analytical lab.

[Mark Tracy]

You can buy 100% teflon squeeze bottles for critical work. I used to use them for diluting to volume for trace metal analysis.

[HW Mueller]

Seems to depend on what is critical.
For trace metal analysis it is common not to use glass containers.
In our hands it was not possible to keep dirt (caused algae formation when using water) out of them over the long run.
Most squeeze bottles have a problem with atmospheric pressure changes....I banned them from the HPLC lab.