Determination of Optimum Operating Parameters for Gas Permeation

....•. ACKNOWLEDGEMENT. DEDICATION. . . . •. TABLE OF CONTEN TS LIST OF TABLES • LIST OF FIGURES .

This area of kinetics has been studied (14) and most of the work has centered around a depletion of molecular oxygen or purging molecular oxygen from the unit dose form.
The universal pres.ence of dissolved gases in liquid vehicles for drug solution has, in some cases, led to adverse effects w ith oxygen sensitive systems. Since most drug moieties are semipolar in nature, they possess chemical groupings such as carbonyls that are susceptible to oxidative effects. In many cases aromaticity, implying unsaturation, is usually some component of drug substances ; therefore, a potential for autoxidation also exists. Because the pi bond system can be easily perturbed by distortion polarization in liquid systems, electron loss (oxidation) can re<).dily occur.
In some cas e s (2 ) , both oxidative and non-ox idative m e chanis m s are op e rative for the same mole cular specie s. R. + Oz __ ....., R -0 -0· Here free radicals react with molecular oxyg en to form peroxy radicals that generate more free radicals.
Here free radicals and p eroxy radicals react to form various inactive compounds.
It can be postulated that if molecular oxygen necessary for the propagation step were eliminated, oxidative processes could be significantly reduced. Therefore, the propagation step assumes major importance in free radical mediated reactions for pharmaceutical systems.
Alterations in the susceptible system can further complicate the problem of stability. Trace impurities, pH changes, and preservatives can alter decomposition rates. Temperature may affect the system in two fashions. With respect to stability, increased temperature results in increased molecular collisions and the availability of molecular oxygen to increase the rate of the propagation step in oxidative decomposition. With increased temperature, however, the solubility of molecular oxygen in the solvent is decreased causin g less allowable o:h.ryg en to react in the propagation step. The affect of increased molecular collisions is accepted as being greater than that of the decreased oxygen availability so that the overall result would be a n increased rate of degradation.
The effect of dis solved oxygen concentration on the autoxidation reactions is not readily apparent (2). Shou (3) has indicated that ( 4 oxygen levels are not usually considered since it is difficult to alter the oxygen concentration with present equipment. Shou stated that, 11 it is impossible to reduce oxygen levels below a critical value necessary for oxidative degradation. 11  Sulfites have proven notorious for this interaction. Although the above processes have been employed as aids in reduction of oxidative decomposition, none have afforded complete protection. To date, the most effective protection has been achieved through employment of a combination of nitrogen flushing and antioxidant addition. Air displacement with layered nitrogen has also been reported to aid protection of oxygen sensitive pharmaceuticals (6), (13 ).
In recent years, interest has developed, and study devoted to, employment of gas permeation as a method to reduce dissolved oxygen levels. Although gas permeation bo protect pharmaceuticals is relativel y new, it has been successfully employed in other areas. Genetelli and Cole (7)  In general the permeability of plastic membranes to gases has been shown to obey Fick ' s Law:

Determination of Flow Rate
The holding tank was charged with distilled deionized water and brought to the desired pressure by nitrogen addition.
After a five minute stabilization period, readings were recorded in milliliters per minute. Results were obtained at pressures ranging from 100 to 1000 pounds in 100 pound intervals.
All pressures were uncorrected and read directly from the gas  Evaluation of gas permeation entails efficiency of gas removal as well as protection afforded a model drug system. If gas permeation is to be considered for industrial use, an effluent flow rate must be achieved which allows a practical, readily adaptable application to current unit processes. Table I indicates, as expected, a direct relationship, between the pressure with which the effluent is forced through the permeator and the flow rate.
If the efficiency of oxygen removal follows a similar pattern, the pressure that allows the greatest flow rate would be considered an optimum operating parameter.
At pressures greater than 1000 psig difficulties may be encountered which would decrease operating efficiency. For example, most present equipment is not rated for high pressure operations.
Also since the permeator shell employed has a pressure rating of 1500 psig, it would be impossible to use higher pressures with this apparatus. The amount of fiber that dissolve s in the effluent is directly relate d to the t e mpe rature and press u re the reby aff e cting the efficiency of the pe r m e ator.  Table II and Table Ill. Study shows that passes through the permeator at all pressures reduce the dissolved oxygen levels significantly. One pass through the permeator reduces the dissolved oxygen levels from 9. 05 ppm to less than 0. 78 ppm as a function of pressure as demonstrated in Table III and Figure 3. If the apparatus were to be employed in a unit process system, the necessity of manually recharging the system for a second pass would have to be avoided or simulated in another manner since this would disrupt the steady flow of a unit process and result in increased cost.
To alleviate this problem two methods may be employed. · First, the permeator length might be increased to allow the solvent a        The effect of reduced dissolved oxygen levels on the degradation rate of a susceptible system was studied using pyrogallol as a model drug . This drug moiety is especially susceptible to oxidative decomposition due to the three adjacent hydroxyl groups and the unsaturated nature of the compound. Table . IV illustrates the rate of degradation of an unprotected system prepared with deionized, distilled water. The rate of degradation is rapid (5. 57 x 1 o-2 days -1 }. Figure 2 shows that the degradation is apparently first order, which is expected for most oxi dative processes. Half of the drug is decomposed in 10. 3 hours and the T90 is 1. 9 hours. Removal of most of the dissolved oxygen in the solvent should retard reaction kinetics since the molecular oxygen concentrati on has an effect on the propagation step. However, since it has b ee n shown that susceptible systems may degrade by a secondary pat h w ay (2) if oxygen is not readily available', the removal of molecular ox y ge n might not afford complete protection.
Tables V throu gh XIII depict the de g radation of pyrog allol in water pr e pared at va r ious pres sur e s and eithe r a sing l e or double pass w ith resultan t various dis s olve d oxyg en lev els.
Since a colorimetric assay was utilized, data is reported as ranges to allow the usual variations in this analytical procedure.
Difficulties and variations of results were further compounds since the as say has been shown to be time dependent. (12) Systems protected via gas penneation have apparent first order degradation. Alt hough the molecular oxygen concentration of single pass systems were less than 1 ppm, degradation occurred.
The extent of the degradation however was significantly less than that of the unprotected system. Thus, single pass systems (less than 1. 0 ppm) do afford protection to a system of pyrogallol since the oxygen available for degradation is considerably less than in unprotected systems.
Study of systems protected by a double pass, producing trace dissolved oxygen leve l s, lead to interesting observations. First, at trace oxygen levels ,, degradation occurs; probably because the drug moiety degrades by a non-oxidative process. Many drugs having primarily oxidative pathways for degradation will degrade by other means as well. The degradation rates however are considerably less and appear to "stabilize" after a slight initial degradation.
(           there is a significant reduction in de gradation due to the depletion of molecular oxygen.
An indication of the protection afforded via gas permeation is the relative protection ratio. If the unprotected system is assigned an index value of unity, a single pass system has an index of 0. 026 and a double pass system an index of 0. 018. This is to say that a single The protection afforded permeated systems is readily apparent from Table XIV and it has been shown that a double pass system decreases degradation sig n ificantly enough to warrant the e1nployment of a second perme ation pass.
IV. CONCLUSIONS I.
Effluent flow rate is directly proportional to the pressure with which the effluent is forced through the permeator.

2.
A single pass of effluent through the permeator will reduce the dis solved oxygen levels in proportion to the resident in the apparatus, or the effluent flow rate. The efficiency of molecular oxygen removal is greatest at slowest flow rates and lowest pressures.

3.
Double pass systems are reduced to trace levels of dissolved oxygen regardless of the flow rate at which they are prepared.

4.
For efficient oxygen removal at acceptable flow rates for industrial processes, the optimum operating parameters for the Permasep(R) would be 1000 psig with two permeators connected in series.

5.
Dissolved oxygen levels of less than 1 ppm reduce pyrogallol degradation considerably although the degradation is not inhibited completely.
6. Trace dissolved oxygen levels reduce pyrogallol degradation significantly, pr ob ably completely, except for degradation by nonoxidative pathways.