Study of local anaesthetics . Part 172 * Comparison of the influence of auxilliary substances on physicochemical parameters of two phenylcarbamic acid derivatives

It this work was studied the influence of polyols (propylene glycol, glycerol and sorbitol) on the physicochemical parameters (partition coefficient and surface tension) and liberation from aqueous solutions with propylene glycol of two derivatives of phenylcarbamic acid. Studied parameters and liberation were influenced by the structure of the studied derivatives and with the type and concentration of polyols.


Introduction
The partition coefficient and the surface tension are physicochemical parameters that considerably influence absorption and effect of the drug.The determination of partition coefficient was studied in many papers.Beside classical shake-flask method of determination, which is in actual practice still used, were developed some new experimental methods [1,2,3,4,5,6,7].
The physicochemical properties and relationship between structure, physicochemical properties and biological activity of potential local anaesthetics drugs from the group of phenylcarbamic acid derivatives were the matter of many studies published in several papers [8,9,10,11,12,13,14,15,16,17,18].
The dosage forms in which the local anaesthetics are often applied are hydrogels.They are used as lubricants e.g. for insertion of catheters.Because the necessary components of hydrogels are humectants, the physicochemical properties were determined in water solution of humectants: propylene glycol (PG), glycerol (GL) and sorbitol (SO) in concentration 5,10,15 a 20%.

Results and Discussion
The two derivatives of phenylcarbamic acid with local anaesthetic effect, with the operative names -substance XXIII Z and XIV were compared.The substance XXIII Z, N-[2-(3-oktyloxyfenylkarbamoyloxy) -ethyl] -pyrrolidiniumchloride, is 16 times more effective in surface anesthesia in comparison with cocaine and 7 times more effective in infiltration anaesthesia in comparison with procaine as standard [19].The substance XIV, N-[2-(3-penthyloxyfenylkarbamoyloxy) -ethyl]piperidiniumchloride is 80 times more effective in surface anesthesia in comparison with cocaine as standard and 135 times more effective in infiltration anaesthesia in comparison with procaine as standard [20].The both substances differ with the structure of molecule, i.e. with substitution of aromatic ring and with the length of alkoxy substituent whereby lipophility is affected.It has been assumed that different structure of substances under investigation can affect the examined physicochemical parameters.Partition coefficient (P) and surface tension ( ) were determined, because both parameters can influence liberation, absorption and drugs action.
From the results (Table 1) appears that the structure of potential drug and used auxilliaries and their concentration influence both physicochemical parameters.The influence of physicochemical parameters on the partition coefficient is bigger than on the surface tension.
Experimental determined values partition coefficients of substance XXIII Z were about 13 -15 times bigger than of substance XIV and confirm higher lipophility of substance XXIII Z.The differences between surface tensions of compared substances were smaller.

Substance
The of XXIII Z substance was about 1.3 times lower in comparison with XIV substance.
Generally humectants with the XXIII Z substance reduce P and increase the , and with the XIV substance reduce both P and .
The influence of polyols and their concentrations on the determined parameters were different.With increased concentration of PG and GL is decreased value of P of XXIII substance.On the contrary SO increases the value of P. With increased concentration of PG is the value increased.The influence of GL and SO is insignificant.With increased concentration of polyols is P of the XIV substance insignificantly decreased.The value is decreased with PG and SO, but only in 15-20% concentration of PG and SO.The GL is without any influence.
From the results it can be concluded that from the humectants the biggest influence on the studied parameters has PG, therefore it was used on the study of in vitro liberation of potential drugs from the solutions.The results of liberation indicate that it was liberated 3 to 5 times less of the substance XXIII Z in comparison with substance XIV (Table 2 and 3).The presence of PG in the sample increased the liberation of substance XXIII and decreased the liberation of substance XIV in comparison with the sample without the humectant.The work confirmed the influence of molecule of potential drugs on the partition coefficient and surface tension and the effect of the type and concentration of auxilliary substances on the physicochemical parameters and the liberation of potential drugs from aqueous solution of PG.

Determination of partition coefficient
Partition coefficient values (P) were determined in the system consisting of noctanol/aqueous phase at 37°C [11].The aqueous phase comprised either pure water or water with 5 , 10, 15 and 20 wt.% of polyol added.The potential drug was determined in the aqueous phase by UV spectrophotometry (XXIII Z at = 235 nm, XIV at = 236 nm) against similarly prepared reference containing no drugs.

Determination of surface tension
Surface tension ( ) was evaluated 24 h after preparation of the solution at a temperature of 20°C in stalagmometer by weighing the drops.It was used 0.1 wt.
% water solutions of potential drug with or without 5 , 10, 15 and 20 wt.% of polyol added.

Determination of liberation
Potential drug was left to permeate at 37 °C through a hydrophilic membrane (19.6 cm 2 ) (Nephrophan, Filmfabrik Wolfen, Germany) into isotonic NaCl solution.
Released drug amounts were determined by spectrophotometry (Philips Pye UV VIS, Unicam Ltd., UK) in the respective intervals [21].
*Part 171: Die Pharmazie in press