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The solubilization of drug in lipids is determined by multiple parameters like interfacial tension, crystal structure, molecular volume, hydrophilicity, charge, chemical environment of media. Theoretical and experimental results of various parameters considered for the present study has been enumerated below.
Van Krevelen's group contribution method was applied to determine solubility of drug in lipids. The three parts of solubility parameter was manually estimated. The solubility parameter of ceftriaxone sodium is 25.18 and its polarity is 0.38. Table no. 1 shows that the calculated total solubility parameters (?t) of solid lipids vary from 18.05 to 20.79 and that of liquid lipids vary from 15.61 to 22.26. Similarly, the polarity (Xp) of the solid lipids vary from 0.07 to 0.31 and that of liquid lipids vary from 0.1 to 0.3. The difference between total solubility parameters of ceftriaxone and various solid lipids range between 4.39 to 7.13 and that of total solubility parameters of ceftriaxone and various liquid lipids range between 2.92 to 9.57 (Table 2).
Similarly, the difference in polarity of the drug and various solid lipids vary from 0.07 to 0.31, while the difference in polarity of the drug and various liquid lipids varies from 0.08 to 0.28. It is also clear from table 2 that the mixing enthalpies of drugs with various solid lipids vary from 5.98 to 22.84, while that of drugs and liquid lipids vary from 2.52 to 25.57.
The chemical structure of 12 lipids are enumerated in Table 1. It also presents the calculated values of three partial solubility parameters and the total solubility parameters and polarity of lipids and the drug.
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The lipids constitute fatty acids of different chain lengths, triglycerides of various structures and mixtures of glycerol esters. Dispersion forces, hydrogen bonding and polar forces determine partial solubility. Dispersion forces are due to the presence of alkyl groups viz., RCH3, > RCH2R, >(CH)R, >C Imwitor 900 > PrecirolATO 5 > stearic acid > Compritol 888 > Softisan 154. Solubility of the liquid lipids with drug was found in following order: Capryol 90 > Lauroglycol FCC > Labrafac PG > Oleic acid > Miglyol 812N > Isopropyl Myristate.
Table 2: The differences of partial solubility parameters, total solubility parameter, mixing enthalpy and polarity between various lipids and drug ceftriaxone
(J??cm?^3 )^(1?2) ??p (J??cm?^3 )^(1?2) ??h (J??cm?^3 )^(1?2) ??t (J??cm?^3 )^(1?2) ?xp (J??cm?^3 )^(1?2) ?HM
(J??cm?^3 )
1 Stearic acid (octadecanoic acid) 1.99 5.78 8.02 6.42 0.28 19.06
2 Compritol 888 pellets
40-60% diesters of behenic acid(glycerly dibehenate) 2.96 6.12 7.26 7.1 0.24 18.55
21-35% triesters of behenic acid (glyceryl tribehenate) 3.06 6.46 9.56 7.91 0.32 26.72
15-23%glyceryl behenate (mono) 2.7 5.18 3.31 5.03 0.1 8.45
Behenic acid 3.23 6.11 8.73 7.84 0.29 23.25
Average 2.98 5.97 7.215 6.97 0.24 19.24
3 Glyceryl mono stearate 2.46 4.33 2.67 4.39 0.07 5.99
4 Imwitor 900(F)P
40-50% glyceryl monostearate 2.46 4.33 2.67 4.39 0.07 5.99
Glyceryl distearate 2.39 5.15 7.01 6.4 0.24 15.26
Average 2.43 4.74 4.84 5.40 0 .155 10.62
5 Precirol ATO 5
Glyceryl palmitostearate 2.39 5.05 6.93 6.32 0.23 14.86
6 Softisan 154 (hydrogenated vegetable oils are mixture of triglycerides of fatty acids 1.72 5.33 9.51 7.13 0.31 22.84
1 Oleic Acid 2.18 5.77 7.98 6.59 0.28 19.07
2 Isopropyl myristate 5.03 4.19 9.67 9.57 0.27 25.57
3 Capryol 90 (propylene glycol monocaprylate (type II)) 1.15 2.22 2.68 2.92 0.08 2.52
4 Lauroglycol FCC(propylene glycol monolaurate (Type I) 1.45 3.4 4.09 3.28 0.13 5.69
5 Labrafac PG (propylene glycol dicaprylate /dicaprate) 1.42 4.57 4.91 4.61 0.18 8.81
6 Miglyol 812N
Glyceryl tricaprylate 2.32 4.05 8.22 6.59 0.26 16.75
Glyceryl tricaprate 2.33 4.56 8.7 6.82 0.28 19.11
Average 2.33 4.30 8.46 6.71 0.27 17.93
??t = difference between total solubility parameter of drug and lipids, ??d =?difference between partial solubility parameter associated with dispersion force of drug and lipid????p ? difference between partial solubility parameter associated polar force of drug and lipid, ??h = difference between partial solubility parameter associated hydrogen bonding of drug and lipid, ?Xp = difference between polarity of drug and lipid,??HM = mixing enthalpy
Solubility of ceftriaxone sodium in various solid lipids and liquid lipids
Solubility of ceftriaxone sodium in solid lipids and liquid lipids is enumerated in table 3 and table 4 respectively. As evident form table 3 the drug has low solubility in most of the tested solid lipids. While the drug was found to be having a maximum solubility of 0.0175%(w/w) in glycerol monostearate among solid lipids, it had a maximum solubility in Capyrol 90 among the liquid lipids.
Currently no known standard method of determination of solubility of drug in lipids has been developed. Hence, a simple method of dissolving the drug in incremental amounts in molten lipid and liquid lipid till no further dissolution is observed, is used to estimate the solubility of drug in lipids. As Ceftriaxone is a hydrophilic drug it was observed that it has poor solubility in lipids but among the six solid lipids (table 3) and six liquid lipids (table 4) it had maximum solubility in Glyceryl mono stearate and Capryol 90 respectively. Solubility of the solid lipids with drug was found in following order: glyceryl mono stearate > Imwitor 900 / PrecirolATO 5/stearic acid > Compritol 888 / Softisan 154. Solubility of the liquid lipids with drug was found in following order: Capryol 90 > Lauroglycol FCC > Labrafac PG > Oleic acid > Miglyol 812N > Isopropyl Myristate. Thus, there is a clear correlation between the experimental results of solubility with the calculated values of solubility parameters using Van Krevelen's group distribution method.
Table 3: Solubility of ceftriaxone sodium in various solid lipids
Solid lipids Melting point 0C Solubility of ceftriaxone sodium
0.0025 %(w/w) 0.0050 %(w/w) 0.0075 %(w/w) 0.0100 %(w/w) 0.0125 %(w/w) 0.0150 %(w/w) 0.0175 %(w/w) 0.0200 %(w/w)
Glyceryl mono stearate 58- 59 Soluble Soluble Soluble Soluble Soluble Soluble Soluble Insoluble
Imwitor® 900 P 54-64 Soluble Soluble Soluble Soluble Soluble Soluble NA NA
Precirol® ATO5 52-56 Soluble Soluble Soluble Soluble Soluble Soluble Insoluble NA
Stearic acid 69-70 Soluble Soluble Soluble Soluble Soluble Soluble Insoluble NA
Compritol® 888 ATO 69-74 Soluble Soluble Soluble Soluble Soluble Insoluble Insoluble NA
Softisan® 154 53-58 Soluble Soluble Soluble Soluble Soluble Insoluble Insoluble NA
Qualitative percentage solubility of ceftriaxone sodium in various molten solid lipid excipients. NA stands for not applicable
Table 4: Solubility of ceftriaxone sodium in various liquid lipids
Liquid lipid Amount of Liquid lipid in (g) required to solubilize 10mg of drug
Capryol 90 (propylene glycol monocaprylate (type II)) 2.59
Lauroglycol FCC(propylene glycol monolaurate (Type I) 3.47
Labrafac PG (propylene glycol dicaprylate /dicaprate) 3.92
Partition coefficients (ratio of the concentration of drug in solid lipid to the concentration of drug in aqueous phase) obtained were presented in fig 2 and fig 3. The partition behaviour of drug in solid lipids (table 5 and fig 3) is evidently found to be decreasing in the following order: glyceryl mono stearate > Imwitor 900 > PrecirolATO 5 > stearic acid > Compritol 888 > Softisan 154, while, that of the drug in liquid lipids (table 6 and fig 4) was found decreasing in following order: Capryol 90 > Lauroglycol FCC > Labrafac PG > Oleic acid > Miglyol 812N > Isopropyl Myristate. Thus, there was a clear association between the partition coefficient determined experimentally with the calculated values of solubility parameters using Van Krevelen's group distribution method.
Lipids with monoglyceride of long chain fatty acids (glyceryl mono stearate, Imwitor 900) and medium chain fatty acids (Capryol 90) exhibited highest partition co-efficient. It was found that with increase in the carbon chain length and number of chains the solubility of the drug decreased. Polar groups in the glyceryl mono stearate facilitate mutual miscibility between glyceryl mono stearate and the drug in comparison to other lipids. Glyceryl mono stearate and Capryol 90 has the best miscibility with ceftriaxone sodium which is evident from the results of partition experiment and the calculated solubility parameters which corroborated each other.
Fig. 2: Apparent Partition coefficient of Ceftriaxone Sodium in Solid Lipids and water
Fig. 3: Apparent Partition coefficient of Ceftriaxone Sodium in Liquid Lipids and water
Table 5 enumerates thermal events of binary mixture of Glycerol Monostearate And Capryol 90, taken in different ratios and exposed to heat at 1000C for 1 hour. The onset, end set and peak temperatures of binary mixture of Glycerol Monostearate And Capryol 90, taken in different ratios are shown in table 5 and fig 4.
Table 5: DSC parameter for binary mixture of glycerol monostearate and capryol 90 following exposure to heat at 1000C for 1 hour
Glycerol monostearate: Capryol 90 Thermal Event Onset (0C) Peak temp (0C) End set temp (0C) WME*(0C)
100:00 Endothermic 62.29 66.23 70.68 3.94
90:10 Endothermic 55.47 59.17 64.15 3.7
85:15 Endothermic 47.14 57.13 62.44 9.99
80:20 Endothermic 52.28 55.98 60.01 3.7
75:25 Endothermic 47.83 53.28 59.19 5.45
70:30 Endothermic 47.25 53.84 59.54 6.59
60:40 Endothermic 49.04 54.66 59.60 5.82
*WME stands for width of melting event
It is evident from solubility parameter and partition coefficient studies that glyceryl mono stearate and capryol 90 were the best suitable lipids for formulation of NLC of ceftriaxone sodium. The two lipids were taken in different ratios and subjected to DSC analysis to determine the ratio for the best binary mixture. Results of DSC study (fig 4) shows that all the binary mixtures exhibit melting points between 500C to 650C. Width of the melting events was considered as the parameter for screening the binary mixtures of glyceryl mono stearate and capryol 90. The blend of solid lipid and liquid lipid which gave the maximum width of melting events was considered as the best binary mixture. The mixture of 85% glyceryl mono stearate and 15% capryol 90 gave the maximum WME 9.990C, hence, was considered the best possible binary mixture. From DSC analysis (table 5) it was also evident that the peak temperature and the onset temperature of the solid lipid glyceryl monostearate was decreasing with increase in the concentration of liquid lipid capryol 90.
Fig 4: DSC analysis of solid lipids and liquid lipids mixed in different ratio
Sample A 100% Glycerol monostearate : 0%Capryol 90; sample B ratio of 90%Glycerol monostearate :10% Capryol 90 ; sample C 85% Glycerol monostearate : 15%Capryol 90; sample D 80% Glycerol monostearate :20% Capryol 90; sample E 75% Glycerol monostearate :25% Capryol 90; sample F70% Glycerol monostearate :30% Capryol 90; sample G 60% Glycerol monostearate : 40%Capryol 90; sample H 0% Glycerol monostearate : 100% Capryol 90
Compatibility drug-excipient studies by FTIR analysis (fig. 5-6):
Compatibility of the drug with glycerol monostearate and capyrol 90 study was conducted by DSC method and FTIR method. Fig 5 shows the DSC curves of drug with glycerol monostearate and capyrol 90 and fig 6 shows the FTIR curves of drug with glycerol monostearate and capyrol 90.
Fig 5: DSC analysis for compatibility studies between drug and lipids
Sample A DSC of ceftriaxone sodium; Sample B DSC of Glyceryl monostearate; Sample C DSC of Capryol 90; Sample D DSC of admixture of ceftriaxone sodium, Glyceryl monostearate and Capryol 90
Fig. 6: FTIR studies for compatibility analysis between drug and lipids
Sample A FTIR of Ceftriaxone Sodium; Sample B FTIR of Glyceryl mono stearate; Sample C FTIR of Capryol 90; Sample D FTIR of admixture of ceftriaxone Sodium, glyceryl monostearate and capryol 90; Sample E comparative study of FTIR of individual drug ceftriaxone, glyceryl monostearate, capryol 90 and admixture of ceftriaxone Sodium, glyceryl monostearate and capryol 90 respectively
Analysis of DSC and FTIR studies clearly proves that there is no significant shift in the melting events including the peak and onset temperature of ceftriaxone sodium. There was no appearance of new endothermic peak suggesting that there was no incompatibility between the drug and the lipid excipient. However, due to likely alterations in mixture geometry, slight changes in peak shape, height and width was noted. Even in FTIR studies it was found that no new dips were note and the admixture of drug and lipids contained all the dips of the functional groups which were present in the drug and both lipids. From both DSC and FTIR analysis it was confirmed that the drug is compatible with the lipid excipient.
Designing of pharmaceutical dosages form using solubility parameter approach has a lot of limitation. Although literature survey shows that the solubility parameter gives appropriate result related to the interaction elements of mixing system but still it is a fact that it considers only the direct contact energy and do not account for other thermodynamic parameters like entropy, free volume of amorphous, etc. The most challenging part of manufacturing of SLNs and NLCs is incorporation of hydrophilic drug into lipid carriers. Moreover, due to high cost of polymers, the solubility parameter method could be used to screen and determine the appropriate solid and liquid lipids required for the specific drug. In this study both theoretical and experimental solubility determination approaches were considered to judge the most capable lipid candidate for the formulation of NLCs. Glyceryl mono stearate as the solid lipid and Capryol 90 as liquid lipid were chosen as the suitable lipids. The lesser the differences between the of total solubility parameter and polarity of the drug and lipid carriers, greater would be the compatibility/miscibility between the drug and lipid carriers. Supplementary studies are essential to assess the pertinent combinations of drugs and excipients for large scale manufacturing. It is evident from the results of theoretical solubility parameters that it goes well with that of experimental analysis.
SCREENING OF LIPIDS USING SOLUBILITY PARAMETER TO DEVELOP. (2019, Dec 04). Retrieved from https://studymoose.com/screening-of-lipids-using-solubility-parameter-to-develop-example-essay
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