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Question

Posted on: April 26 2017

Preparation with 10% gabapentin and 0.5% doxepin in unbuffered cetomacrogolcreme is not stable.

We have made this preparation for the same patient with 8% gabapentin and 0.5% doxepin and we got no complaints. With the increase of 8% to 10% gabapentin we got crystals in our preparation after a few hours and thus became unusable. Do you have any idea how we could handle this? We have already adjusted the pH to 7.3 because this would be ideal for gabapentin, but here too we got crystals.

Answer

The solution of your problem is complicated by ambiilities about the solubility in water of gabapentin. A reference gives "freely soluble in water or in acidic and alkaline solutions". Freely soluble   means that 1 g of 1 to 10 ml of water is required. Another reference says that 0.45 g dissolves in 100 ml of water (4.5 mg/ml). This is a much lower solubility. On the other hand, Sigma-Aldrich gives 10 mg/ml. At a pH = 7.5 The solubility is higher than 100 mg/ml

If you are preparing an 8% cream then 20 capsules are used. I count 600 mg per capsule and this means 12 g of mass minus 100 g cetomacrogol cream. 88 g of cream remains. This corresponds to about 60   g of water.   You do not have crystal formation. This gives as solubility for Gabapentin 1 g in approximately 7.5 ml of water. If we adopt this as solubility in water, we need 10 g gabapentin 75   ml of water. Even though these reflections are speculative, we can still presuppose that with a 10% cream the solubility is exceeded because we have only 59 ml of water

I found in the literature an example of a 6% cream in a creamy base analogous to hydrophilic anionic cream TMF

The composition is: Gabapentin 6 g, glycerin 15 ml and hydrophilic anionic cream up to 100 g; The preparation consists of making gabapentin finely and then rubbing with glycerin into a soft homogeneous paste. Then it is gradually blended with hydrophilic anionic cream.  

One does not explain why it is working in this way and the Gabapentin BV is not solved in the preceding. The control of the smoothness of the cream is highlighted. If necessary, treatment with the ointment grinder is recommended.  

Perhaps the crystallization you determine can be avoided by making the water less acidic. Now we will have to be careful as there is also Doxepin HCl, which will be converted to Doxepin base and it has a solubility of 32 mg per litre.

The molecular mass of the gabapentin is about double like of NaHCO3. If we now have the additional 2 G gabapentin (from 8% to 10%) Converting to salt then 1 g of NaHCO3 would be required. If this is not enough, an additional quantity of 0.5 g, possibly followed by 1 x 0.5 g, can be added.