Drug Solubilization

CHAPTE R 9

Drug Solubilization Symbols and Terminology CCT DF IF IND ION IPM L1695 LIM ME M159 MNT PG SC SEDDS w/w W

caprylic-capric triglyceride oil drug solubilization dilution factor drug solubilization overall interfacial contribution factor (calculated interfacial factor) indomethacin α-ionone isopropyl myristate oil sucrose laurate R (+)-limonene oil microemulsions PEG-7 glyceryl cocoate peppermint oil propylene glycol drug solubilization capacity self-emulsifying drug delivery systems weight per weight water

9.1 Introduction Microemulsions (MEs) have gained much attention in the area of drug solubilization and delivery due to their low cost of manufacture, high-solubilization capacity (SC), spontaneous formation, thermodynamic stability, transparency and low viscosity, enhanced stability of the encapsulated drug, high-absorption rates, high-drug SC, improved oral bioavailability and protection against enzymatic hydrolysis, and ability to enclose both hydrophilic as well as hydrophobic drugs [1–4]. In addition to oral and intravenous delivery, MEs are amenable to prolonged and targeted delivery through ophthalmic, dental, pulmonary, vaginal, and topical routes [5]. The ME small droplet diameter, which enables high mobility in the vehicle and adhesion to the skin surface, is also effective for cutaneous drug delivery and enhanced drug permeation [6]. Kumar et al. [7] reviewed the effect of formulation components of ME, trends in selection of new excipients constituting the oil phase, surfactants and cosurfactants. ME systems show significant improvement in topical delivery of antifungal, antiviral, antiinflammatory, antioxidant, local anesthetics, etc. Numerous mechanisms have been suggested [8] for improved transdermal drug delivery from MEs, which include: high drug loading capacity, penetration enhancing effect of the ME components, possible entrance Sugar Esters Microemulsions. http://dx.doi.org/10.1016/B978-0-12-811653-1.00009-3 © 2017 Elsevier Inc. All rights reserved.

351

352  Chapter 9 of ME components into the skin as monomers increasing the solubility of the drug in the skin, the microstructure of the MEs which provides a large surface area of drug transfer, and the last mechanism relies on the phase transition of MEs, which provides a possibility for producing supersaturated systems with high-thermodynamic activity. In recent in vitro and in vivo studies it was reported that MEs offer higher oral absorption, bioavailability, digestion speed and extent compared to luteolin suspensions [9]. Molecular dynamic simulations were applied to model the lipidic nanoscale droplets that form when self-emulsifying drug-delivery systems (SEDDS) disperse into MEs in the gastrointestinal tract. The hydrophobic cyclosporine loading capacity of droplets yielded a negligible influence of drug molecules on the droplet nanostructure; increasing the drug load merely resulted in increased drug exposure to the aqueous environment [10]. The various aspects of MEs with respect to the field of nonsteroidal antiinflammatory drugs were reviewed by Singh et al. [11]. A true and continuing need is present for the development of effective drug delivery systems for poorly water-soluble drugs to enhance their absorption and bioavailability [12]. Drug solubility is a key parameter during the processes related to design and development of new pharmaceutical prescription formulae. Indomethacin (IND) is a nonsteroidal antiinflammatory drug with analgesic (pain-killing) potential, used in the treatment of rheumatoid arthritis, osteoarthritis, spondylitis and other disorders [13]. The rate of oral absorption of IND, a poorly soluble, highly permeable drug, is often controlled by the dissolution rate in the gastrointestinal tract. Therefore, together with its permeability, the solubility and dissolution behavior of IND are key determinants of its oral bioavailability. IND was solubilized for oral delivery in a ME based on mixed surfactants containing soybean oil, phosphatidylcholine/sodium oleate/Eumulgin HRE40 as the surfactant mixture and water or buffer solution as the aqueous phase. High concentrations of IND were incorporated (i.e., 62.3 mg/mL). A small retention effect was observed for IND that was explained by the partitioning properties of the drug [14]. In previous studies we reported on the solubilization of azithromycin [15], celecoxib [16], cephalexin [17], and diclofenac [18,19] on MEs based on mixed nonionic surfactants including sugar esters. In this study, we report on the SC of IND in MEs composed of water/ sucrose laurate/PEG-7 glycerol cocoate/oil systems.

9.2 Experimental 9.2.1 Materials The sucrose laurate (L1695) was obtained from Mitsubishi-Kasei Food Corp. (Mie, Japan). The purity of combined lauric acid equals 95%, the ester compositions are 80% monoester and 20% di-, tri- and polyester, HLB equals 16. PEG-7 glycerol cocoate (M159) (HLB

Drug Solubilization  353 equals 13) was obtained from BASF Corporation (Gurnee, IL, United States). Peppermint oil (MNT), R (+)-limonene (LIM) (98%), α-ionone (ION), isopropyl myristate (IPM), propylene glycol (PG), and IND (see Fig. 9.1) were purchased from Sigma Chemicals Co. (St. Louis, United States). Caprylic-capric triglyceride (CCT), a food, pharmaceutical, and cosmetic grade medium chain triglyceride containing 60 wt% C7 and 40 wt% C9, was obtained from Stepan Europe (Voreppe, France). All of the components were used as supplied without further purification. Triple distilled water was used.

9.2.2  Determination of Drug SC Three grams of ME were prepared in a test tube and then a small amount of IND (about 10 mg in each step) was added and dissolution was performed by mixing through a vortex in a water bath at 45°C for 30 min and then stored at 25°C in a water bath. Samples that remained transparent for at least 5 days were loaded step-wise with additional IND to its maximum solubilization. The appearance of turbidity, or a precipitate, indicates that the MEs were drug saturated (or supersaturated). No further drug loading in such samples was done. The dissolved amount of IND was estimated by calculating the accumulate weight of IND which was added before the appearance of turbidity, or a precipitate, after the hold in a water bath at 25°C for at least 5 days.

9.2.3  IND Solubilization Evaluation The amount (mg/g ME) of solubilized IND within the ME formulation at a given aqueous phase content (wt%) is defined as the IND SC. Three different parameters related to IND maximum solubilization are determined in order to better understand the role of the interface and the dilution by aqueous phase on the SC. The first is the observed SC change factor (CF) (CFfn ) estimated using Eq. (9.1) by dividing the measured SC at each water volume fraction (SCfn ) , by the measured SC at the previous water volume fraction (SCfn-1 ). CFfn =

SCfn SCfn-1

(9.1)

H3CO

Cl

O HO

N CH3

O

Fig. 9.1 Chemical structure of indomethacin.

354  Chapter 9 We also determined the “calculated dilution factor” using Eq. (9.2) from the decrease in the SC as a function of dilution from one water volume fraction to the next. 1 - fn DFfn = (9.2) 1 - fn -1 We termed a value “overall interfacial contribution factor” (IF), which is strongly dependent on several structural and interfacial composition factors. The overall interfacial contribution factor is calculated using Eq. (9.3) by dividing the observed SC CF (CFfn ) by the dilution factor (DF) (DFfn ) at each water volume fraction: CFfn (9.3) DFfn When the overall interfacial contribution factor is smaller than unity, the DF is dominant, it dictates the SC behavior and the interface plays a minor role in the SC, meaning that the drug is located mainly in the oil phase. When the overall interfacial contribution factor equals unity, the interface and DFs contribute evenly, indicating that the drug is located partly at the interface and partly at the oil phase. When the overall interfacial contribution factor is higher than unity, the interface plays a dominant role where the drug is mostly located at the interface [20,21]. As the overall interfacial contribution factor grows, the interface plays a more significant role in the solubilization of the drug. The variations in the overall interfacial contribution factor value along the aqueous phase dilution line could indicate the structural transition affecting IND solubilization. IFfn =

9.3  Results and Discussion 9.3.1  IND SC in ME Components The SCs of IND at 25°C in the different components used for the preparation of various MEs used in the solubilization of IND are presented in Table 9.1. As shown in this table, the solubility of the hydrophobic drug in water is very small compared to the other components. The solubility of the drug in PG is about five times higher than that of water. Mixing PG with water reduces the maximum solubility of IND to that of water. It seems that the interactions between the hydroxyl groups on PG and those on the drug contribute to the improved SC of PG. Cosolvency [22] is a frequently used method to increase the drug solubility by several orders of magnitude and it is relatively simple. The preferential solvation for IND in PG + water binary mixtures was recently studied [23]. It was found that it is conjecturable that in water-rich mixtures the hydrophobic hydration around the aromatic rings and methyl groups of the drug plays a relevant role in the solvation. The higher drug solvation in cosolvent-rich mixtures could be due mainly to polarity effects. Here IND would be acting as a Lewis acid with PG molecules because these cosolvents are

Drug Solubilization  355 Table 9.1: Solubilization capacity (SC) of indomethacin in different components used in the preparation of microemulsions System Name Water (W) Propylene glycol (PG) W/PG W/L1695/M159 W/PG/L1695/M159 Peppermint oil (MNT) R (+)-limonene (LIM) Isopropyl myristate (IPM) Caprylic-capric triglyceride (CCT) IPM + MNT IPM + LIM CCT + MNT CCT + LIM

Mixing Ratio (wt/wt)

2/1

1/1 1/1 1/1 1/1

SC (mg/g) 3 16 4 14 15 34 13 9 15 73 13 37 12

more basic than water. In another study [24], the solubility of IND was determined by using the stirred flask method as a function of temperature and cosolvent composition in some ethanol + PG mixtures. The results indicate that the dissolution mechanism is dependent on the cosolvent mixture composition. IND solubility in PG + water mixtures was also studied using the extended Hildebrand solubility approach [25]. It was found that the solubility is a function of the mixtures' solubility parameters [25]. The equilibrium solubilities of IND in PG + water binary mixtures were also determined at various temperatures [26]. It was found that the driving mechanism for IND solubility in the water-rich mixtures was the entropy, probably due to water-structure loss around nonpolar moieties of the drug and for the PG-rich mixtures it was the enthalpy, probably due to its better solvation of the drug. Thermodynamic parameters were calculated and showed spontaneity of the solubility process (negative free energy change). Entropy and enthalpy changes were positive, suggesting a high degree of randomness of the system and an endothermic dissolution process [27]. IND release in relation to the concentration of PG was also reported [28] and it was found that the concentration of PG influences the rate of IND release from gels. The percutaneous absorption and penetration of IND from oil-in-water MEs were enhanced by changing the composition of cosurfactants PG/transcutol compared to ethanol/transcutol [29]. MNT and its mixtures with other oils solubilize the highest amount of IND. The solubilities of the drug in LIM and its mixtures with other oils are lower compared to those of MNT. It seems that the interactions between the hydroxyl groups in the components of the MNT with the oxygens and hydroxyl groups of the drug favor its solubility and improve it compared to the cyclic LIM. The maximum solubilization of IND in CCT is higher than that in IPM.

356  Chapter 9 These results indicate that there are three factors affecting the maximum solubilization of IND in any components. These factors are I. The presence of oxygens and/or hydroxyl groups in the component (i.e., MNT compared to LIM). II. The molecular volume of the oil (i.e., LIM compared to IPM). III. The three-dimensional configuration in space of the component (i.e., IPM compared to CCT). In the following sections, we present the maximum SC of IND in various formulated MEs based on the components presented in Table 9.1.

9.3.2  Water/Sucrose Laurate/PEG-7 Glycerol Cocoate/MNT Fig. 9.2 shows the phase diagram of the system water/sucrose laurate/PEG-7 glycerol cocoate/MNT. The ratio of sucrose laurate/PEG-7 glycerol cocoate equals unity. The one-phase ME region is designated by 1ϕ and the multiphase region is designated by the heterogeneous region. The samples were measured along the N65 dilution line where the weight ratio of (sucrose laurate + PEG-7 glycerol cocoate)/oil equals 65/35. Table 9.2 presents the sample composition along the N65 dilution line for different aqueous phase contents in single oil formulated MEs. The SC of IND at 25°C as a function of aqueous phase content along the dilution line N65 is presented in Table 9.3 and Fig. 9.3. The SC decreases from 46 mg/g ME at water content equal to 0 wt% to about 29 mg/g at water content equal to 30 wt% in the first region; in the second region the SC decreases dramatically from 29 mg/g at water content equal to 30 wt% to 18 mg/g ME at water content L1695/M159 = 1

1f

N65

Heterogeneous region Water

MNT

Fig. 9.2 Phase diagram of the system water/sucrose laurate (L1695)/PEG-7 glyceryl cocoate (M159)/ peppermint oil (MNT). The one-phase region is designated by 1ϕ, and the multiphase region is designated by the heterogeneous region. N65 is the dilution line where the mixing ratio (w/w) of (sucrose laurate + PEG-7 glyceryl cocoate)/peppermint oil equals 65/35.

Drug Solubilization  357 Table 9.2: Samples composition along the N65 dilution line for single oil formulated microemulsions Aqueous Phase (wt%)

L1695 (wt%)

M159 (wt%)

Oil (wt%)

0 10 20 30 40 50 60 70 0 90

32.5 29.25 26 22.75 19.5 16.25 13 9.75 32.5 3.25

32.5 29.25 26 22.75 19.5 16.25 13 9.75 32.5 3.25

35 31.5 28 24.5 21 17.5 14 10.5 35 3.5

Table 9.3: Maximum measured solubilization capacity (SC) of indomethacin, the observed ­solubilization capacity change factor (CF), dilution factor (DF), and interfacial contribution factor (IF) along the dilution line N65 in the system water/sucrose laurate + PEG-7 glycerol ­cocoate/peppermint oil at 25°C Water Content (wt%)

SC

CF

DF

IF

0 10 20 30 40 50

46 43 28 29 25 18

0.95 0.65 1.02 0.84 0.75

0.900 2.111 1.526 1.345 1.256

1.06 0.31 0.67 0.63 0.59

The mixing ratio (w/w) of sucrose laurate + PEG-7 glycerol cocoate equals unity.

equal to 50 wt%. At aqueous phase content equal to zero (wt%), the SC of IND molecules is the highest due to its presence in the mixed surfactant and oil phase. IND is embedded at the interface (and in the core of the micelles) and does contribute to the assembly of the reversed micelles. Upon dilution with the aqueous phase, the drug maximum SC is affected by the aqueous phase addition and interfacial packing. As the dilution with an aqueous phase progresses, the SC of the ME decreases. The decrease in the SC is affected by the dilution and the swelling factors. IND solubilization was not influenced solely by the DF or the structural changes, but also by the nature of the interface along the dilution line. MNT acts as a penetration enhancer of IND, as reported [22]. It was also reported that MNT combined with PG, azone, N-methylpyrrolidone and oleic acid can be used as a penetration enhancer in the transdermal preparation of IND [30]. The overall interfacial contribution factor (calculated interfacial factor) (IF) shown in Fig. 9.4 decreases for aqueous phase

358  Chapter 9 50 45

SC (mg/g)

40 35 30 25 20 15 0

20 40 Water content (wt%)

60

Fig. 9.3 The solubilization capacity (SC) of indomethacin (mg drug/g microemulsion) as a function of water content along the dilution line N65 in the phase diagrams is presented in Fig. 9.2 at 25°C in the system water/sucrose laurate/PEG-7 glyceryl cocoate/peppermint oil. The mixing ratio of sucrose laurate/PEG-7 glyceryl cocoate equals unity. The lines in this figure and the following are presented as guides to the eye. 1.2 1.0

IF

0.8 0.6 0.4 0.2 0

10

20 30 40 Water content (wt%)

50

60

Fig. 9.4 Interfacial contribution factor (IF) as a function of aqueous phase content along the dilution line N65 in the water/sucrose laurate/PEG-7 glyceryl cocoate/peppermint oil system presented in Fig. 9.2.

Drug Solubilization  359 contents up to 20 wt%, confirming that the dilution contributes negatively to the SC. For aqueous phase contents above 20 up to 30 wt%, the calculated IF increases, indicating that the dilution has a positive effect on the solubilization. This change in the solubility is attributed to possible interfacial change in the ME microstructure (i.e., transition from water-in-oil droplets to bicontinuous microstructure). The calculated IF values decrease for aqueous phase contents above 30 wt%, indicating that changes in the orientation of the surfactant molecules are occurring in this bicontinuous microstructure. This decrease in the calculated IF indicates that IND molecules are still entrapped at the interface and that the DF is dominant over the IFs. Similar behaviors of solubilized drugs in MEs were reported elsewhere [20,21].

9.3.3  Water/Sucrose Laurate/PEG-7 Glycerol Cocoate/LIM LIM enhanced the IND permeation, indicating that cyclic monoterpenes are able to alter the barrier property of stratum corneum. LIM was also recognized [31–37] as an enhancer for the transdermal penetration into full-thickness rat skin of the lipophilic drug IND and a hydrophilic permeant (urea) as estimated by an in vitro technique. Percutaneous absorption of IND from Pluronic F127 gels in rats was significantly improved by the addition of LIM and IPM [38] to the gel formulation. In this study, we also solubilized IND in the system water/sucrose laurate/PEG-7 glycerol cocoate/LIM. Fig. 9.5 presents the phase diagram of the system. The mixing ratio of sucrose laurate/PEG-7 glycerol cocoate equals unity. The one-phase ME region is designated by 1ϕ and the multiphase region is designated by the heterogeneous region. The samples were measured along the L1695/M159 = 1

1f

N65

Heterogeneous region Water

LIM

Fig. 9.5 Phase diagram of the system: water/sucrose laurate (L1695)/PEG-7 glyceryl cocoate (M159)/ R (+)-limonene oil (LIM). The one-phase region is designated by 1ϕ, and the multiphase region is designated by the heterogeneous region. N65 is the dilution line where the mixing ratio (w/w) of (sucrose laurate + PEG-7 glyceryl cocoate)/R (+)-limonene oil equals 65/35.

360  Chapter 9 N65 dilution line where the weight ratio of (sucrose laurate + PEG-7 glycerol cocoate)/ oil equals 65/35 (see Table 9.2 for compositions). The SC of IND at 25°C as a function of aqueous phase content along the dilution line N65 is presented in Table 9.4 and Fig. 9.6. Two different regions are observed in the SC presented in Fig. 9.6. The SC increases from a 21 mg/g ME at water content equal to 0 wt% to a 24 mg/g ME at water content equal to 10 wt% in the first region. In the second region, the SC decreases from a 24 mg/g ME at water content equal to 10 wt% to 10 mg/g ME at water content equal to 50 wt%. The increase in the drug SC for water contents below 10 wt% indicates that the dilution with the aqueous phase screws more drug in the interface due to rearrangements and packing changes of mixed surfactants at the interface. As the dilution with an aqueous phase Table 9.4: Maximum measured solubilization capacity (SC) of indomethacin, the observed solubilization capacity CF, DF, and interfacial contribution factor (IF) along the dilution line N65 in the system water/sucrose laurate + PEG-7 glycerol cocoate/R (+)-limonene at 25°C Water Content (wt%)

SC

CF

DF

IF

0 10 20 30 40 50

21 24 21 18 13 10

1.13 0.86 0.87 0.75 0.76

0.900 2.111 1.526 1.345 1.256

1.26 0.41 0.57 0.56 0.60

The mixing ratio (w/w) of sucrose laurate + PEG-7 glycerol cocoate equals unity.

24

SC (mg/g)

20

16

12

8 0

20 40 Water content (wt%)

60

Fig. 9.6 The solubilization capacity (SC) of indomethacin (mg drug/g microemulsion) as a function of water content along the dilution line N65 in the phase diagrams is presented in Fig. 9.5 at 25°C in the system water/sucrose laurate/PEG-7 glyceryl cocoate/R (+)-limonene. The weight ratio of (sucrose laurate/PEG-7 glyceryl cocoate) equals unity.

Drug Solubilization  361 1.4 1.2

IF

1.0 0.8 0.6 0.4 0

10

20 30 40 Water content (wt%)

50

60

Fig. 9.7 Interfacial contribution factor (IF) as a function of aqueous phase content along the N65 dilution line in the water/sucrose laurate/PEG-7 glyceryl cocoate/R (+)-limonene system presented in Fig. 9.5.

progresses, the SC of the ME decreases. The decrease in the SC is affected by the dilution and the swelling factors. As mentioned earlier, IND solubilization is influenced by the DF and by the nature of the interface along the dilution line. The calculated IF shown in Fig. 9.7 decreases for aqueous phase contents up to 20 wt%, confirming that the dilution contributes negatively to the SC. For aqueous phase contents above 20 up to 50 wt%, the calculated IF increases indicating that although the drug solubility decreases with water addition still the dilution has a positive effect on the drug organization at the interface. This change in the solubility is attributed to a structural change in the MEs (i.e., transition from water-in-oil droplets to bicontinuous microstructure).

9.3.4  Water/Sucrose Laurate/PEG-7 Glycerol Cocoate/ION Fig. 9.8 presents the phase diagram of the system water/sucrose laurate/PEG-7 glycerol cocoate/ ION. The ratio of sucrose laurate/PEG-7 glycerol cocoate equals unity. The one-phase ME region is designated by 1ϕ and the multiphase region is designated by the heterogeneous region. The samples were measured along the N65 dilution line (see Table 9.2 for compositions) where the weight ratio of (sucrose laurate + PEG-7 glycerol cocoate)/oil equals 65/35. The SC of IND at 25°C as a function of aqueous phase content along the dilution line N65 is presented in Table 9.5 and Fig. 9.9. The SC decreases from 37 mg/g ME at water content equal to 0 wt% to about 10 mg/g at water content equal to 20 wt%, and then phase separation occurs. This decrease in the SC indicates that aqueous phase swelling induces less favorable surfactant-drug interaction at the interface. The calculated IF increases, indicating that the dilution with water has a positive effect on the arrangement of the drug at the interface between surfactant and oil.

362  Chapter 9 L1695/M159 = 1

1f

N65

Heterogeneous region Water

ION

Fig. 9.8 Phase diagram of the system: water/sucrose laurate (L1695)/PEG-7 glyceryl cocoate (M159)/αionone (ION). The one-phase region is designated by 1ϕ, and the multiphase region is designated by the heterogeneous region. N65 is the dilution line where the mixing ratio (w/w) of (sucrose laurate + PEG-7 glyceryl cocoate)/α-ionone equals 65/35. Table 9.5: Maximum measured solubilization capacity (SC) of indomethacin, the observed solubilization capacity change factor (CF), dilution factor (DF), and interfacial contribution factor (IF) along the dilution line N65 in the system water/sucrose laurate/PEG-7 glycerol cocoate/α-ionone at 25°C Water Content (wt%)

SC

CF

DF

IF

0 10 20

37 11 10

0.31 0.93

0.900 2.111

0.34 0.44

The mixing ratio (w/w) of sucrose laurate/PEG-7 glycerol cocoate equals unity.

9.3.5  Water/Sucrose Laurate/PEG-7 Glycerol Cocoate/IPM The effects of the ME containing IPM and cosolvents, including PG, used for the preparation of vehicles containing Carbopol gels on the liberation of IND were evaluated [39]. It was found that the presence of the ME and cosolvents affects the permeation rate and the amount of liberated drug. The ME acts as an accelerator of IND liberation in less viscous Carbopol gels. Fig. 9.10 presents the phase diagram of the system water/sucrose laurate/PEG-7 glycerol cocoate/IPM. The ratio of sucrose laurate/PEG-7 glycerol cocoate equals unity. The onephase ME region is designated by 1ϕ and the multiphase region is designated by the heterogeneous region. The samples were measured along the N65 dilution line where the weight ratio of (sucrose laurate + PEG-7 glycerol cocoate)/oil equals 65/35 (see Table 9.2

Drug Solubilization  363 40 35

SC (mg/g)

30 25 20 15 10 0

10 20 Water content (wt%)

30

Fig. 9.9 The solubilization capacity (SC) of indomethacin (mg drug/g microemulsion) as a function of water content along the dilution line N65 in the phase diagram is presented in Fig. 9.8 at 25°C in the system water/sucrose laurate/PEG-7 glyceryl cocoate/α-ionone. The mixing ratio of (sucrose laurate/PEG-7 glyceryl cocoate) equals unity. L1695/M159 = 1

1f

N65

Heterogeneous region Water

IPM

Fig. 9.10 Phase diagram of the system: water/sucrose laurate (L1695)/PEG-7 glyceryl cocoate (M159)/ isopropyl myristate oil (IPM). The one-phase region is designated by 1ϕ, and the multiphase region is designated by the heterogeneous region. N65 is the dilution line where the mixing ratio (w/w) of (sucrose laurate + PEG-7 glyceryl cocoate)/isopropyl myristate equals 65/35.

for compositions). The SC of IND at 25°C as a function of aqueous phase content along the dilution line N65 is presented in Table 9.6 and Fig. 9.11. Two different regions are observed in the SC presented in Fig. 9.11. The SC increases from a 17 mg/g ME at water content equal to 0 wt% to a 22 mg/g ME at water content equal to 10 wt% in the first region. In the second region, the SC decreases from a 22 mg/g ME at water content equal to 10 wt% to a 14 mg/g

364  Chapter 9 Table 9.6: Maximum measured solubilization capacity (SC) of indomethacin, the observed solubilization capacity change factor (CF), dilution factor (DF), and interfacial contribution factor (IF) along the dilution line N65 in the system water/sucrose laurate/PEG-7 glycerol cocoate/ isopropyl myristate at 25°C Water Content (wt%)

SC

CF

DF

IF

0 10 20 30 40

17 22 19 17 14

1.25 0.88 0.91 0.79

0.900 2.111 1.526 1.345

1.39 0.42 0.59 0.59

The mixing ratio (w/w) of sucrose laurate/PEG-7 glycerol cocoate equals unity.

25

SC (mg/g)

20

15

10 0

10

20 30 Water content (wt%)

40

50

Fig. 9.11 The solubilization capacity (SC) of indomethacin (mg drug/g microemulsion) as a function of water content along the dilution line N65 in the phase diagrams is presented in Fig. 9.10 at 25°C in the system water/sucrose laurate/PEG-7 glyceryl cocoate/isopropyl myristate. The weight ratio of (sucrose laurate/PEG-7 glyceryl cocoate) equals unity.

ME at water content equal to 40 wt%. The increase in the drug SC for water contents below 10 wt% indicates that the dilution with aqueous phase permits more drug to be placed at the interface due to reorganizations and packing variations of mixed surfactants. As the dilution with an aqueous phase advances, the SC of the ME decreases. The decrease in the SC is influenced by the dilution and the swelling factors. The calculated IF shown in Fig. 9.12 decreases for aqueous phase contents up to 20 wt%, confirming that the dilution contributes adversely to the SC. For aqueous phase contents above 20 up to 40 wt%, the calculated IF increases, indicating that although the drug solubility decreases with water addition,

Drug Solubilization  365 1.4 1.2

IF

1.0 0.8 0.6 0.4 0

10

20 30 Water content (wt %)

40

50

Fig. 9.12 Interfacial contribution factor (IF) as a function of aqueous phase content along the dilution line N65 in the water/sucrose laurate/PEG-7 glyceryl cocoate/isopropyl myristate system presented in Fig. 9.10.

nevertheless the dilution has a constructive effect on the drug arrangement at the interface. This change in the solubility is ascribed to ME structural alterations (i.e., transition from water-in-oil droplets to a bicontinuous microstructure).

9.3.6 Water + PG/Sucrose Laurate/PEG-7 Glycerol Cocoate/IPM Fig. 9.13 presents the phase diagram of the system water + PG/sucrose laurate/PEG-7 glycerol cocoate/IPM. The mixing ratio of sucrose laurate/PEG-7 glycerol cocoate equals unity and that of water/PG equals twofold. The one-phase ME region is designated by 1ϕ and the multiphase region is designated by the heterogeneous region. The samples were measured along the N65 dilution line where the weight ratio of (sucrose laurate + PEG-7 glycerol cocoate)/oil equals 65/35 (see Table 9.2 for components compositions). The SC of IND at 25°C as a function of aqueous phase content along the dilution line N65 is presented in Table 9.7 and Fig. 9.14. The SC remains practically indifferent to aqueous phase contents below 20 wt%, and then decreases for aqueous phase contents above 20 wt%. The calculated IF shown in Fig. 9.15 decreases for aqueous phase contents up to 20 wt%, proving that the dilution contributes unfavorably to the SC. For aqueous phase contents above 20 up to 50 wt%, the calculated IF increases, indicating that although the drug solubility decreases with water addition, nevertheless the dilution has a constructive effect on the drug arrangement at the interface. This change in the solubility is ascribed to ME structural alterations (i.e., transition from water-in-oil droplets to bicontinuous microstructure).

366  Chapter 9 L1695/M159 = 1

1f

N65

Heterogeneous region Water/PG = 2

IPM

Fig. 9.13 Phase diagram of the system: water + propylene glycol/sucrose laurate/PEG-7 glyceryl cocoate/ isopropyl myristate at 25°C. The mixing ratios (w/w) of (sucrose laurate/PEG-7 glyceryl cocoate) and (water/propylene glycol) equal unity and twofold, respectively. The one-phase region is designated by 1ϕ, and the multiphase region is designated by the heterogeneous region. N65 is the dilution line where the mixing ratio (w/w) of (sucrose laurate + PEG-7 glyceryl cocoate)/isopropyl myristate equals 65/35.

Table 9.7: Maximum measured solubilization capacity (SC) of indomethacin, the observed solubilization capacity change factor (CF), dilution factor (DF), and interfacial contribution factor (IF) along the dilution line N65 in the system water + propylene glycol/sucrose laurate/PEG-7 glycerol cocoate/isopropyl myristate at 25°C Aqueous Phase Content (W + PG) (wt%)

SC

CF

DF

IF

0 10 20 30 40 50

28 29 29 22 18 17

1.01 1.00 0.75 0.81 0.95

0.900 2.111 1.526 1.345 1.256

1.13 0.47 0.49 0.61 0.76

The mixing ratio (w/w) of sucrose laurate/PEG-7 glycerol cocoate equals unity and that of water/propylene glycol is twofold.

In Figs. 9.14 and 9.15 which compare the solubilization parameters of IND in the systems water/sucrose laurate/PEG-7 glycerol cocoate/IPM and water + PG/sucrose laurate/PEG-7 glycerol cocoate/IPM, we observe that adding PG to the system improves the SC of IND. This behavior is attributed to the presence of hydroxyl groups in the PG that attract drug molecules to the interface. Similar behaviors of IND in the presence of PG in the system were reported earlier in this chapter [22–29].

Drug Solubilization  367 35

W W+PG

SC (mg/g)

30 25 20 15 10 0

20 40 Aqueous phase content (wt%)

60

Fig. 9.14 The solubilization capacity (SC) of the indomethacin (mg drug/g microemulsion) as a function of aqueous phase content along the dilution line N65 at 25°C in the systems water + propylene glycol/sucrose laurate/PEG-7 glyceryl cocoate/isopropyl myristate and water/sucrose laurate/ PEG-7 glyceryl cocoate/isopropyl myristate (added for comparative purposes). The mixing ratios of (sucrose laurate/PEG-7 glyceryl cocoate) and (water/propylene glycol) equal unity and twofold, respectively.

1.4

W W+PG

IF

1.2 1.0 0.8 0.6 0.4 0

20 40 Aqueous phase content (wt%)

60

Fig. 9.15 Interfacial contribution factor (IF) as a function of aqueous phase content along the dilution line N65 in the systems water + propylene glycol/sucrose laurate/PEG-7 glyceryl cocoate/isopropyl myristate and water/sucrose laurate/PEG-7 glyceryl cocoate/isopropyl myristate (added for comparative purposes). The mixing ratios of (sucrose laurate/PEG-7 glyceryl cocoate) and (water/ propylene glycol) equal unity and twofold, respectively.

368  Chapter 9

9.3.7  Water/Sucrose Laurate/PEG-7 Glycerol Cocoate/CCT Medium chain triglyceride oil (CCT)-based SEDDS were prepared by dissolving Cremophor EL, Tween 20, Tween 80 and Span 80 (1% or 5%) in the oil for the solubilization of the ophthalmic drug IND [40,41]. In this study the system water/sucrose laurate/PEG-7 glycerol cocoate/CCT was also investigated for the solubilization of IND. Fig. 9.16 presents the phase diagram of the system. The mixing ratio of sucrose laurate/PEG-7 glycerol cocoate equals unity. The one-phase ME region is designated by 1ϕ and the multiphase region is designated by the heterogeneous region. The samples were measured along the N65 dilution line where the weight ratio of (sucrose laurate + PEG-7 glycerol cocoate)/oil equals 65/35 (see Table 9.2 for component compositions). The SC of IND at 25°C as a function of aqueous phase content along the dilution line N65 is presented in Table 9.8 and Fig. 9.17. The SC decreases from a 27 mg/g ME at water content equal to 0 wt% to 7 mg/g at water content equal to 10 wt%, and steadies at a 7 mg/g ME for water content above 10 wt% up to water content equal to 40 wt%, where phase separation occurs. The overall interfacial contribution factor (IF) shown in Fig. 9.18 increases with aqueous phase content, proving that the dilution contributes constructively to the SC. The monotonic increase in calculated IF designates that although the drug solubility decreases with water addition, yet the dilution has a positive effect on the drug arrangement at the interface.

9.3.8  Effect of Oil on Drug SC In Figs. 9.19 and 9.20, we grouped the IND SC and interfacial calculated factor (IF) in the previously studied systems to better present the effect of oil on the maximum solubilization of the drug in the MEs. As shown in Fig. 9.19 the order of decreasing solubilization is as L1695/M159 = 1

1f N65

Heterogeneous region Water

CCT

Fig. 9.16 Phase diagram of the system: water/sucrose laurate (L1695)/PEG-7 glyceryl cocoate (M159)/ caprylic-capric triglyceride oil (CCT). The one-phase region is designated by 1ϕ, and the multiphase region is designated by the heterogeneous region. N65 is the dilution line where the mixing ratio (w/w) of (sucrose laurate + PEG-7 glyceryl cocoate)/caprylic-capric triglyceride equals 65/35.

Drug Solubilization  369 Table 9.8: Maximum measured solubilization capacity (SC) of indomethacin, the observed solubilization capacity change factor (CF), dilution factor (DF), and interfacial contribution factor (IF) along the dilution line N65 in the system water/sucrose laurate/PEG-7 glycerol cocoate/caprylic-capric triglyceride at 25°C Water Content (wt%)

SC

CF

DF

IF

0 10 20 30 40

27 7 7 7 7

0.25 0.96 1.07 1.00

0.900 2.111 1.526 1.345

0.28 0.46 0.70 0.74

The mixing ratio (w/w) of sucrose laurate/PEG-7 glycerol cocoate equals unity.

30

SC (mg/g)

25 20 15 10 5

0

10

20 30 Water content (wt%)

40

50

Fig. 9.17 The solubilization capacity (SC) of the indomethacin (mg drug/g microemulsion) as a function of water content along the dilution line N65 in the phase diagram is presented in Fig. 9.16 at 25°C in the system sucrose laurate/PEG-7 glyceryl cocoate/caprylic-capric triglyceride. The mixing ratio of (sucrose laurate/PEG-7 glyceryl cocoate) equals unity.

follows: peppermint > LIM > ION > IPM > CCT. These results indicate that the three factors affecting the maximum solubilization of IND mentioned previously—the presence of oxygens and/or hydroxyl groups in the component, the molecular volume of the oil, and the three-dimensional configuration in space of the component—are the factors determining the maximum SC. It is clear that the molecular volume of the oil is the dominant factor, knowing that the order of increasing molecular volume is: LIM < peppermint < CCT < ION < IPM. The other two factors, the presence of oxygens and/or hydroxyl groups in the component and the three-dimensional configuration in space, play secondary roles. A synergetic effect exists between the three factors that determines the maximum SC of the drug in a given system. In the following sections, we present the IND SC in mixed surfactant/mixed oil systems.

370  Chapter 9 0.8

IF

0.6

0.4

0.2

0

10

20 30 Water content (wt%)

40

50

Fig. 9.18 Interfacial contribution factor (IF) as a function of aqueous phase content along the dilution line N65 in the system sucrose laurate/PEG-7 glyceryl cocoate/caprylic-capric triglyceride. The mixing ratio of (sucrose laurate/PEG-7 glyceryl cocoate) equals unity. 50 MNT LIM ION IPM CCT

SC (mg/g)

40

30

20

10

0 0

10

20 30 40 Water content (wt%)

50

60

Fig. 9.19 The solubilization capacity (SC) of indomethacin (mg drug/g microemulsion) as a function of water content along the dilution line N65 at 25°C in the systems: water/sucrose laurate/PEG-7 glyceryl cocoate/oil for peppermint oil (MNT), R (+)-limonene (LIM), α-ionone (ION), isopropyl myristate (IPM), and caprylic-capric triglyceride (CCT). The mixing ratio of (sucrose laurate/PEG-7 glyceryl cocoate) equals unity.

Drug Solubilization  371 1.5 MNT LIM IPM CCT

IF

1.2

0.9

0.6

0.3 0

10

20 30 40 Water content wt%)

50

60

Fig. 9.20 Interfacial contribution factor (IF) as a function of aqueous phase content along the dilution line N65 in the systems water/sucrose laurate/PEG-7 glyceryl cocoate/oil for peppermint oil (MNT), R (+)-limonene (LIM), isopropyl myristate (IPM) and caprylic-capric triglyceride (CCT). The mixing ratio of (sucrose laurate/PEG-7 glyceryl cocoate) equals unity.

9.3.9  Water/Sucrose Laurate/PEG-7 Glycerol Cocoate/IPM/MNT Fig. 9.21 presents the phase diagram of the system water/sucrose laurate/PEG-7 glycerol cocoate/IPM/MNT. The mixing ratios of sucrose laurate/PEG-7 glycerol cocoate and IPM/ MNT equal unity. The one-phase ME region is designated by 1ϕ and the multiphase region is designated by the heterogeneous region. The samples were measured along the N65 dilution line where the weight ratio of (sucrose laurate + PEG-7 glycerol cocoate)/mixed oils equals 65/35 and the N50 dilution line where the weight ratio of (sucrose laurate + PEG-7 glycerol cocoate)/mixed oils equals 50/50 (see Tables 9.9 and 9.10 for component compositions). IND SC along the N65 and N50 dilution lines are presented in Tables 9.11 and 9.12 and in Fig. 9.22. We identified three major regions in the SC curve along the N65 dilution line separated by SC deflection boundaries. At aqueous phase content equal to zero, the SC of IND molecules is the highest due to it being in the mixed oil phase. IND is embedded at the interface (and in the core of the micelles) and does contribute to the assembly of the reversed micelles. Upon dilution with the aqueous phase, the solubilization is affected by aqueous phase addition and interfacial packing. As the dilution with an aqueous phase progresses, the SC of the ME decreases. The decrease in the SC is affected by the dilution and the swelling factors. IND solubilization was not influenced solely by the DF or the structural changes, but also by the nature of the interface along the dilution line shown in Fig. 9.21. The same behavior is observed along the N50 dilution line with the difference that the drug SC is higher along the

372  Chapter 9 L1695/M159 = 1

1f

N65 N50

Heterogeneous region Water

IPM/MNT = 1

Fig. 9.21 Phase diagram of the system: water/sucrose laurate (L1695)/PEG-7 glyceryl cocoate (M159) isopropyl myristate (IPM)/peppermint oil (MNT) at 25°C. The mixing ratios (w/w) of (sucrose laurate/PEG-7 glyceryl cocoate) and (isopropyl myristate/peppermint oil) equal unity. The onephase region is designated by 1ϕ, and the multiphase region is designated by the heterogeneous region. N65 is the dilution line where the mixing ratio (w/w) of (sucrose laurate + PEG-7 glyceryl cocoate)/(isopropyl myristate + peppermint oil) equals 65/35. N50 is the dilution line where the mixing ratio (w/w) of (sucrose laurate + PEG-7 glyceryl cocoate)/(isopropyl myristate + peppermint oil) equals 50/50.

Table 9.9: Sample composition along the N65 dilution line for mixed oil systems Aqueous Phase (wt%)

L1695 (wt%)

M159 (wt%)

Oil1 (wt%)

Oil2 (wt%)

0 10 20 30 40 50 60 70 0 90

32.5 29.25 26 22.75 19.5 16.25 13 9.75 32.5 3.25

32.5 29.25 26 22.75 19.5 16.25 13 9.75 32.5 3.25

17.5 15.75 14 12.25 10.5 8.75 7 5.25 17.5 1.75

17.5 15.75 14 12.25 10.5 8.75 7 5.25 17.5 1.75

N50 dilution line due to the presence of less surfactant and more space for the drug to screw at the interface. Less surfactant is advantageous for drug solubilization in this case but phase separation occurs at 40 wt% water content. The calculated IF presented in Fig. 9.23 decreases for aqueous phase content below 20 wt%, confirming that the dilution contributes negatively to the SC. For aqueous phase contents between 20 and 40 wt%, the calculated IF increases, indicating that the dilution has a positive effect on the solubilization. The calculated IF values

Drug Solubilization  373 Table 9.10: Sample composition along the N50 dilution line for mixed oil systems Aqueous Phase (wt%)

L1695 (wt%)

M159 (wt%)

Oil1 (wt%)

Oil2 (wt%)

0 10 20 30 40 50 60 70 0 90

25 22.5 20 17.5 15 12.5 10 7.5 25 2.5

25 22.5 20 17.5 15 12.5 10 7.5 25 2.5

25 22.5 20 17.5 15 12.5 10 7.5 25 2.5

25 22.5 20 17.5 15 12.5 10 7.5 25 2.5

Table 9.11: Maximum measured solubilization capacity (SC) of indomethacin, the observed s­ olubilization capacity change factor (CF), dilution factor (DF), and interfacial contribution ­factor (IF) along the dilution line N65 in the system water/sucrose laurate/PEG-7 glycerol ­cocoate/isopropyl myristate/peppermint oil at 25°C Water Content (wt%)

SC

CF

DF

IF

0 10 20 30 40 50 60 70 80 90

29 27 24 25 20 14 10 10 11 10

0.93 0.90 1.02 0.81 0.68 0.74 1.01 1.09 0.91

0.900 2.111 1.526 1.345 1.256 1.204 1.169 1.145 1.127

1.03 0.43 0.67 0.60 0.54 0.61 0.87 0.95 0.80

The mixing ratios of (sucrose laurate/PEG-7 glycerol cocoate) and (isopropyl myristate/peppermint oil) equal unity.

Table 9.12: Maximum measured solubilization capacity (SC) of indomethacin, the observed s­ olubilization capacity change factor (CF), dilution factor (DF), and interfacial contribution ­factor (IF) along the dilution line N50 in the system water/sucrose laurate/PEG-7 glycerol ­cocoate/isopropyl myristate/peppermint oil at 25°C Water Content (wt%)

SC

CF

DF

IF

0 10 20 30 40

35 28 30 24 18

0.79 1.06 0.81 0.74

0.900 2.111 1.526 1.345

0.88 0.50 0.53 0.55

The mixing ratios of (sucrose laurate/PEG-7 glycerol cocoate) and (isopropyl myristate/peppermint oil) equal unity.

374  Chapter 9 35

N65 N50

SC (mg/g)

30 25 20 15 10 0

20

40 60 Water content (wt%)

80

100

Fig. 9.22 The solubilization capacity (SC) at 25°C of indomethacin (mg drug/g microemulsion) as a function of water content along the dilution lines N65 and N50 presented in the phase diagram in Fig. 9.21 in the system water/sucrose laurate/PEG-7 glyceryl cocoate/isopropyl myristate/peppermint oil. The mixing ratios of sucrose laurate/PEG-7 glyceryl cocoate and isopropyl myristate/peppermint oil equal unity.

1.2 N65 N50

IF

1.0

0.8

0.6

0.4 0

20

40 60 Water content (wt%)

80

100

Fig. 9.23 Interfacial contribution factor (IF) as a function of aqueous phase content along the dilution lines N65 and N50 in the water/sucrose laurate/PEG-7 glyceryl cocoate/isopropyl myristate/peppermint oil. The mixing ratios of sucrose laurate/PEG-7 glyceryl cocoate and isopropyl myristate/peppermint oil equal unity.

Drug Solubilization  375 decrease again for aqueous phase content between 40 and 50 wt%, indicating changes in the orientation of the surfactant molecules in the bicontinuous region. This behavior indicates that IND molecules are still entrapped at the interface and that the IFs are dominant over the DF. In the oil-in-water MEs, the mixed oils are entrapped in the aqueous phase and their content (together with the surfactant) progressively decreases. The oil-in-water interface is a hydrophilic interface that is less capable of accommodating the lipophilic IND molecules close to the head groups. The IND has to be squeezed between the surfactant tails; the resulting total solubilization load decreases. The calculated IF values reveal that, in spite of the structural limitations, the interfacial solubilization is a very dominant factor. The strong DF would have dropped the SC very dramatically, and with the very low oil content with such dilution one can expect minimal solubilization of the IND. However, the solubilization is not zero (Fig. 9.23). Similar behaviors of solubilized drugs in MEs were reported elsewhere [21,22]. The calculated IF behavior along the N65 dilution line reveals the structural transitions from water-in-oil to bicontinuous to oil-in-water microstructures. Fig. 9.24 presents a schematic presentation of drug localization along the N65 dilution line.

9.3.10  Water/Sucrose Laurate/PEG-7 Glycerol Cocoate/IPM/LIM Fig. 9.25 presents the phase diagram of the system water/sucrose laurate/PEG-7 glycerol cocoate/ IPM/LIM. The mixing ratios of sucrose laurate/PEG-7glycerol cocoate and IPM/LIM equal unity. The one-phase ME region is designated by 1ϕ and the multiphase region is designated by the heterogeneous region. The samples were measured along the N65 dilution line where the weight ratios of (sucrose laurate/PEG-7 glycerol cocoate)/mixed oils equal 65/35 (see Table 9.9 for samples composition). The SC of IND as a function of aqueous phase content along the dilution line N65 at 25°C is presented in Table 9.13 and Fig. 9.26. The SC decreases from a 29 mg/g ME at water content equal to 0 wt% to a 21 mg/g at water content equal to 30 wt% in the

Fig. 9.24 Schematic presentation (not to scale) of structural transitions and drug localization along the N65 dilution line.

376  Chapter 9 L1695/M159 = 1

1f

N65

Heterogeneous region Water

IPM/LIM = 1

Fig. 9.25 Phase diagram of the system: water/sucrose laurate (L1695)/PEG-7 glyceryl cocoate (M159)/ isopropyl myristate (IPM)/R (+)-limonene (LIM) at 25°C. The mixing ratios (w/w) of sucrose laurate/PEG-7 glyceryl cocoate and isopropyl myristate/R (+)-limonene equal unity. The one-phase region is designated by 1ϕ, and the multiphase region is designated by the heterogeneous region. N65 is the dilution line where the mixing ratio (w/w) of (sucrose laurate + PEG-7 glyceryl cocoate)/ (isopropyl myristate + R (+)-limonene) equals 65/35. Table 9.13: Maximum measured solubilization capacity (SC) of indomethacin, the observed s­ olubilization capacity change factor (CF), dilution factor (DF), and interfacial contribution ­factor (IF) along the dilution line N65 in the system water/sucrose laurate/PEG-7 glycerol ­cocoate/isopropyl myristate/R (+)-limonene at 25°C Water Content (wt%)

SC

CF

DF

IF

0 10 20 30 40 50 60 70 80 90

29 27 25 21 17 10 11 10 7 7

0.94 0.91 0.87 0.81 0.59 1.03 0.97 0.66 1.04

0.900 2.111 1.526 1.345 1.256 1.204 1.169 1.145 1.127

1.04 0.43 0.57 0.61 0.47 0.86 0.83 0.58 0.92

The mixing ratios of (sucrose laurate/PEG-7 glycerol cocoate) and (isopropyl myristate/R (+)-limonene) equal unity.

first region. In the second region, the SC decreases dramatically from 17 mg/g at water content equal to 40 wt% to a 10 mg/g ME at water content equal to 70 wt%; then the amount of drug solubilized decreases to a 7 mg/g ME at water content of 90 wt% in the third region. The calculated IF presented in Fig. 9.27 decreases for aqueous phase contents below 20 wt%, confirming that the dilution contributes negatively to the SC. For aqueous phase contents

Drug Solubilization  377 30

SC (mg/g)

25

20

15

10

5 0

20

40 60 Water content (wt%)

80

100

Fig. 9.26 The solubilization capacity (SC) at 25°C of indomethacin (mg drug/g microemulsion) as a function of water content along the dilution line N65 in the phase diagrams is presented in Fig. 9.25 in the system water/sucrose laurate/PEG-7 glyceryl cocoate/isopropyl myristate/R (+)-limonene. The mixing ratios (sucrose laurate/PEG-7 glyceryl cocoate) and (isopropyl myristate/R (+)-limonene) equal unity.

1.2

IF

1.0

0.8

0.6

0.4 0

20

40 60 Water content (wt%)

80

100

Fig. 9.27 Interfacial contribution factor (IF) as a function of aqueous phase content along the dilution line N65 in the system water/sucrose laurate/PEG-7 glyceryl cocoate/isopropyl myristate/R (+)-limonene. The mixing ratios (sucrose laurate/PEG-7 glyceryl cocoate) and (isopropyl myristate/R (+)-limonene) equal unity.

378  Chapter 9 between 20 and 40 wt%, the calculated IF increases, indicating that the dilution has a positive effect on the solubilization. The calculated IF values decrease again for aqueous phase contents between 40 and 50 wt%, indicating changes in the orientation of the surfactant molecules in the bicontinuous region. The calculated IF increases for water contents between 50 and 70 wt% and then decreases up to 80 wt%, and then increases. This behavior indicates that IND molecules are still entrapped at the interface and that the IFs are dominant over the DF. In the oil-in-water MEs, the mixed oils are entrapped in the aqueous phase and its content (together with the surfactant) progressively decreases. The IF behavior along the N65 dilution line reveals the structural transitions from water-in-oil to bicontinuous to oil-in-water microstructures presented clearly in Fig. 9.24.

9.3.11  Water/Sucrose Laurate/PEG-7 Glycerol Cocoate/IPM/ION Fig. 9.28 presents the phase diagram of the system water/sucrose laurate/PEG-7 glycerol cocoate/IPM/ION. The mixing ratios of sucrose laurate/PEG-7 glycerol cocoate and IPM/ ION equal unity. The one-phase ME region is designated by 1ϕ and the multiphase region is designated by the heterogeneous region. The samples were measured along the N65 dilution line where the weight ratios of (sucrose laurate + PEG-7 glycerol cocoate)/(IPM + ION) equal 65/35 (see Table 9.9 for sample composition). The SC of IND at 25°C as a function of aqueous phase content along the dilution line N65 is presented in Table 9.14 and Fig. 9.29. The SC decreases from a 39 mg/g ME at water content equal to 0 wt% to 18 mg/g at water content equal to 20 wt% in the first region. In the second region, the SC decreased from L1695/M159 = 1

1f

N65

Heterogeneous region Water

IPM/ION = 1

Fig. 9.28 Phase diagram of the system: water/sucrose laurate (L1695)/PEG-7 glyceryl cocoate (M159)/ isopropyl myristate (IPM) + α-ionone (ION) at 25°C. The mixing ratios (w/w) of sucrose laurate/ PEG-7 glyceryl cocoate and isopropyl myristate/α-ionone equal unity. The one-phase region is designated by 1ϕ, and the multiphase region is designated by the heterogeneous region. N65 is the dilution line where the mixing ratio (w/w) of (sucrose laurate + PEG-7 glyceryl cocoate)/(isopropyl myristate + α-ionone) equals 65/35.

Drug Solubilization  379 Table 9.14: Maximum measured solubilization capacity (SC) of indomethacin, the observed s­ olubilization capacity change factor (CF), dilution factor (DF), and interfacial contribution ­factor (IF) along the dilution line N65 in the system water/sucrose laurate/PEG-7 glycerol ­cocoate/isopropyl myristate/α-ionone at 25°C Water Content (wt%)

SC

CF

DF

IF

0 10 20 30 40 50 60 70 80 90

39 29 18 21 18 15 12 12 7 3

0.74 0.62 1.17 0.87 0.86 0.78 1.00 0.58 0.43

0.900 2.111 1.526 1.345 1.256 1.204 1.169 1.145 1.127

0.83 0.29 0.76 0.65 0.68 0.64 0.86 0.51 0.38

The mixing ratios of (sucrose laurate/PEG-7 glycerol cocoate) and (isopropyl myristate/α-ionone) equal unity.

40 35

SC (mg/g)

30 25 20 15 10 5 0 0

20

40 60 Water content (wt%)

80

100

Fig. 9.29 The solubilization capacity (SC) of indomethacin (mg drug/g microemulsion) as a function of water content along the dilution line N65 in the phase diagrams is presented in Fig. 9.28 at 25°C in the system water/sucrose laurate/PEG-7 glyceryl cocoate/isopropyl myristate + α-ionone. The mixing ratios of (sucrose laurate/PEG-7 glyceryl cocoate) and (isopropyl myristate/α-ionone) equal unity.

18 mg/g at water content equal to 20 wt% to a 12 mg/g ME at water content equal to 70 wt%, and then the amount of drug solubilized decreased to a 3 mg/g ME at water content of 90 wt% in the third region. The calculated IF presented in Fig. 9.30 decreases for aqueous phase content below 20 wt%, confirming that the dilution contributes negatively to the SC. For aqueous phase contents

380  Chapter 9 1.0

IF

0.8

0.6

0.4

0.2 0

20

40 60 Water content (wt%)

80

100

Fig. 9.30 Interfacial contribution factor (IF) as a function of aqueous phase content along the dilution line N65 in the system water/sucrose laurate/PEG-7 glyceryl cocoate/isopropyl myristate + α-ionone. The mixing ratios of (sucrose laurate/PEG-7 glyceryl cocoate) and (isopropyl myristate/α-ionone) equal unity.

between 20 and 40 wt%, the calculated IF increases, indicating that the dilution has a positive effect on the solubilization. The calculated IF values decrease again for aqueous phase contents between 40 and 50 wt%, indicating changes in the orientation of the surfactant molecules in the bicontinuous region. The same observed changes were sharper in the LIMbased system. The calculated IF decreases for water contents between 50 and 60 wt% and then increases up to 70 wt%, and then decreases. This behavior indicates that IND molecules are still entrapped at the interface and that the IFs are dominant over the DF. In the oil-inwater MEs, the mixed oils are entrapped in the aqueous phase and its content (together with the surfactant) progressively decreases. Again, the IF behavior along the N65 dilution line reveals the structural transitions from water-in-oil to bicontinuous to oil-in-water microstructures, clearly presented in Fig. 9.24. Fig. 9.31 presents the SC of IND in sucrose laurate/PEG-7 glycerol cocoate/IPM/oil2 for the three oils peppermint, LIM and ION as the second oil. These results indicate that the two factors affect the maximum solubilization of IND in the presence of cyclic oil added to IPM used in the formulation of the MEs. These factors are the presence of hydroxyl groups in the cyclic oil and the molecular volume of the oil. It is clear here that the molecular volume of the oil is the dominant factor, knowing that the order of increasing molecular volume is: LIM < peppermint < ION. The other factor, the presence of hydroxyl groups in the oil, plays a secondary role. A synergetic effect exists between these two factors that determines the maximum SC of the drug in a given system.

Drug Solubilization  381 40

IPM-MNT IPM-LIM IPM-ION

SC (mg/g)

30

20

10

0 0

20

40 60 Water content (wt%)

80

100

Fig. 9.31 The solubilization capacity (SC) of the indomethacin (mg drug/g microemulsion) as a function of water content along the dilution line N65 at 25°C in the systems: water/sucrose laurate/PEG-7 glyceryl cocoate/isopropyl myristate + oil2 for peppermint oil (MNT), R (+)-limonene (LIM), and αionone (ION) as Oil2. The mixing ratios of (sucrose laurate/PEG-7 glyceryl cocoate) and (isopropyl myristate/oil2) equal unity.

9.3.12  Water/Sucrose Laurate/PEG-7 Glycerol Cocoate/CCT/MNT Fig. 9.32 presents the phase diagram of the system water/sucrose laurate/PEG-7 glycerol cocoate/CCT/MNT. The mixing ratios of sucrose laurate/PEG-7 glycerol cocoate and CCT/ MNT equal unity. The one-phase ME region is designated by 1ϕ and the multiphase region is designated by the heterogeneous region. The samples were measured along the N65 dilution line where the weight ratio of (sucrose laurate/PEG-7 glycerol cocoate)/(CCT + MNT) equals 65/35 (see Table 9.9 for sample composition). The SC of IND at 25°C as a function of aqueous phase content along the dilution line N65 is presented in Table 9.15 and Fig. 9.33. The SC increases from a 42 to 46 mg/g ME at water content equal to 0 to 10 wt%, and then it decreases from a 46 mg/g ME at water content equal to 10 wt% to a 13 mg/g ME at water content equal to 60 wt%. The calculated IF presented in Fig. 9.34 decreases for aqueous phase contents below 20 wt%, confirming that the dilution contributes negatively to the SC. For aqueous phase contents above 20 up to 60 wt%, the calculated IF increases, indicating that the dilution has a positive effect on the solubilization.

9.3.13  Water/Sucrose Laurate/PEG-7 Glycerol Cocoate/CCT/LIM Fig. 9.35 presents the phase diagram of the system water/sucrose laurate/PEG-7 glycerol cocoate/CCT/LIM. The mixing ratios of sucrose laurate/PEG-7 glycerol cocoate and CCT/ LIM equal unity. The one-phase ME region is designated by 1ϕ and the multiphase region

382  Chapter 9 L1695/M159 = 1

1f

N65

Heterogeneous region Water

CCT/MNT = 1

Fig. 9.32 Phase diagram of the system: water/sucrose laurate (L1695)/PEG-7 glyceryl cocoate (M159)/ caprylic-capric triglyceride (CCT)/peppermint oil (MNT) at 25°C. The mixing ratios (w/w) of sucrose laurate/PEG-7 glyceryl cocoate and caprylic-capric triglyceride/peppermint oil equal unity. The one-phase region is designated by 1ϕ, and the multiphase region is designated by the heterogeneous region. N65 is the dilution line where the mixing ratio (w/w) of (sucrose laurate + PEG-7 glyceryl cocoate)/(caprylic-capric triglyceride + peppermint oil) equals 65/35. Table 9.15: Maximum measured solubilization capacity (SC) of indomethacin, the observed ­solubilization capacity change factor (CF), dilution factor (DF), and interfacial contribution ­factor (IF) along the dilution line N65 in the system water/sucrose laurate/PEG-7 glycerol ­cocoate/caprylic-capric triglyceride/peppermint oil at 25°C Water Content (wt%)

SC

CF

DF

IF

0 10 20 30 40 50 60

42 46 29 28 21 17 13

1.08 0.64 0.95 0.77 0.80 0.79

0.900 2.111 1.526 1.345 1.256 1.204

1.20 0.30 0.62 0.57 0.64 0.65

The mixing ratios of (sucrose laurate/PEG-7 glycerol cocoate) and (caprylic-capric triglyceride/peppermint oil) equal unity.

is designated by the heterogeneous region. The samples were measured along the N65 and N50 dilution lines where the weight ratios of (sucrose laurate + PEG-7 glycerol cocoate)/ (CCT + LIM) equal 65/35 and 50/50, respectively (see Tables 9.9 and 9.10 for sample composition). The SC of IND at 25°C as a function of aqueous phase content along the dilution lines N65 and N50 are presented in Tables 9.16 and 9.17 and Fig. 9.36. As shown in Fig. 9.36, the IND SC decreases with water content along the N65 and N50 dilution line. In the case of CCT, the SC along the N65 dilution line is higher than that along the N50 dilution line, indicating that the three-dimensional arrangement of CCT in space opens more space for

Drug Solubilization  383 50

SC (mg/g)

40

30

20

10

0 0

20

40 Water content (wt%)

60

Fig. 9.33 The solubilization capacity (SC) at 25°C of indomethacin (mg drug/g microemulsion) as a function of water content along the dilution line N65 in the phase diagrams is presented in Fig. 9.32 in the system water/sucrose laurate/PEG-7 glyceryl cocoate/caprylic-capric triglyceride/peppermint oil. The mixing ratios of (sucrose laurate/PEG-7 glyceryl cocoate) and (caprylic-capric triglyceride/ peppermint oil) equal unity. 1.2

IF

1.0 0.8 0.6 0.4 0.2 0

20

40 Water content (wt%)

60

Fig. 9.34 Interfacial contribution factor (IF) as a function of aqueous phase content along the dilution line N65 in the system water/sucrose laurate/PEG-7 glyceryl cocoate/caprylic-capric triglyceride/ peppermint oil. The mixing ratios of (sucrose laurate/PEG-7 glyceryl cocoate) and (caprylic-capric triglyceride/peppermint oil) equal unity.

384  Chapter 9 L1695/M159 = 1

1f

N65 N50

Heterogeneous region Water

CCT/LIM = 1

Fig. 9.35 Phase diagram of the system: water/sucrose laurate (L1695)/PEG-7 glyceryl cocoate (M159)/ caprylic-capric triglyceride (CCT)/R (+)-limonene (LIM) at 25°C. The mixing ratios (w/w) of L1695/M159 and CCT/LIM equal unity. The one-phase region is designated by 1ϕ, and the multiphase region is designated by the heterogeneous region. N65 is the dilution line where the mixing ratio (w/w) of (sucrose laurate + PEG-7 glyceryl cocoate)/(caprylic-capric triglyceride + R (+)-limonene) equals 65/35. N50 is the dilution line where the mixing ratio (w/w) of (sucrose laurate + PEG-7 glyceryl cocoate)/(caprylic-capric triglyceride + R (+)-limonene) equals 50/50. Table 9.16: Maximum measured solubilization capacity (SC) of indomethacin, the observed s­ olubilization capacity change factor (CF), dilution factor (DF), and interfacial contribution ­factor (IF) along the dilution line N65 in the system water/sucrose laurate/PEG-7 glycerol ­cocoate/caprylic-capric triglyceride/R (+)-limonene at 25°C Water Content (wt%)

SC

CF

DF

IF

0 10 20 30 40

42 31 21 21 18

0.74 0.67 1.00 0.88

0.900 2.111 1.526 1.345

0.82 0.32 0.65 0.65

The mixing ratios of (sucrose laurate/PEG-7 glycerol cocoate) and (caprylic-capric triglyceride/R (+)-limonene) equal unity.

Table 9.17: Maximum measured solubilization capacity (SC) of indomethacin, the observed ­solubilization capacity change factor (CF), dilution factor (DF), and interfacial contribution ­factor (IF) along the dilution line N50 in the system water/sucrose laurate/PEG-7 glycerol ­cocoate/caprylic-capric triglyceride/R (+)-limonene at 25°C Water Content (wt%) 0 10 20 30 40

SC

CF

DF

IF

27 24 7 7 7

0.89 0.27 1.03 1.03

0.900 2.111 1.526 1.345

0.99 0.13 0.67 0.77

The mixing ratios of (sucrose laurate/PEG-7 glycerol cocoate) and (caprylic-capric triglyceride/R (+)-limonene) equal unity.

Drug Solubilization  385 45 N65 N50

40

SC (mg/g)

35 30 25 20 15 10 5 0

20 Water content (wt%)

40

Fig. 9.36 The solubilization capacity (SC) of indomethacin (mg drug/g microemulsion) at 25°C as a function of water content along the dilution lines N65 and N50 in the phase diagrams is presented in Fig. 9.35 in the system water/sucrose laurate (L1695)/PEG-7 glyceryl cocoate (M159)/capryliccapric triglyceride (CCT)/R (+)-limonene. The weight ratios of (sucrose laurate/PEG-7 glyceryl cocoate) and (caprylic-capric triglyceride/R (+)-limonene) both equal unity.

the drug at the interface in the presence of a high amount of surfactants along N65 compared to N50. This behavior is the opposite of that observed in the presence of IPM presented in Fig. 9.22. It should be noted here also that, in the case of IPM, the second oil was peppermint while here the second oil is LIM. Fig. 9.37 presents the interfacial calculated factors along the N65 and N50 dilution lines. It is clear that the oil interactions at the interface, the interactions between oils and surfactants, and drug interactions with both oils and surfactants are the determinant factors of maximum drug solubilization. Fig. 9.38 presents the SC of IND in water/sucrose laurate/PEG-7 glycerol cocoate/CCT/ oil2 for the two oils peppermint and LIM as the second oil. These results indicate that the molecular volume of the oil2 is the dominant factor affecting the maximum SC of IND, knowing that the order of increasing molecular volume is: LIM < peppermint. It is clear that increasing the molecular volume of the oil2 decreases the SC of the drug. The behavior of these systems based on CCT is different from that of the systems based on IPM, due to the difference in the three-dimensional arrangement of the oil. Fig. 9.39 presents the SC of IND in water/sucrose laurate/PEG-7 glycerol cocoate/oil1/ peppermint for the oils IPM and CCT as the first oil. These results indicate that the threedimensional arrangement of the oil1 at the interface is the dominant factor affecting the maximum SC of IND, knowing that IPM is a linear oil and that CCT is forklike. It is clear

386  Chapter 9 1.0

N65 N50

IF

0.8

0.6

0.4

0.2 0

20 Water content (wt%)

40

Fig. 9.37 Interfacial contribution factor (IF) as a function of aqueous phase content along the dilution line N65 in the system water/sucrose laurate (L1695)/PEG-7 glyceryl cocoate (M159)/caprylic-capric triglyceride (CCT)/R (+)-limonene. The weight ratios of (sucrose laurate/PEG-7 glyceryl cocoate) and (caprylic-capric triglyceride/R (+)-limonene) equal unity.

50 CCT-MNT CCT-LIM

SC (mg/g)

40

30

20

10

0 0

20 40 Water content (wt%)

60

Fig. 9.38 The solubilization capacity (SC) of indomethacin (mg drug/g microemulsion) as a function of water content along the dilution line N65 at 25°C in the systems water/sucrose laurate/PEG-7 glyceryl cocoate/caprylic-capric triglyceride/oil2 for peppermint oil (MNT) and R (+)-limonene (LIM) as oil2. The mixing ratios of sucrose laurate/PEG-7 glyceryl cocoate and caprylic-capric triglyceride/oil2 equal unity.

Drug Solubilization  387 50 IPM-MNT CCT-MNT

45 40

SC (mg/g)

35 30 25 20 15 10 0

20

40 60 Water content (wt%)

80

100

Fig. 9.39 The solubilization capacity (SC) of indomethacin (mg drug/g microemulsion) as a function of water content along the dilution line N65 at 25°C in the system water/sucrose laurate/PEG-7 glyceryl cocoate/oil1/peppermint oil for isopropyl myristate (IPM) and caprylic-capric triglyceride (CCT) as oil2. The mixing ratios of sucrose laurate/PEG-7 glyceryl cocoate and oil1/peppermint oil equal unity.

that the forklike arrangement permits more drugs at the interface. The same behavior is observed also with LIM as the second oil in the presence of IPM and CCT as the first oil, as shown in Fig. 9.40.

9.4 Conclusions IND was solubilized in different MEs based on mixed nonionic surfactants including sugar esters and different oils. From the study we are able to conclude the following: • • •

• •

MEs significantly improve the SC of IND compared to its solubility in the separated components forming the MEs. Adding PG to the ME forming components improves the solubility of IND compared to PG free systems. The presence of oxygens and/or hydroxyl groups in the component, their molecular volume and the three-dimensional configuration in space have a synergetic effect on solubilizing IND. The amount of surfactant present in the system has a major role to play in solubilizing the drug. This effect is also influenced by the type of oil present in the system. Mixing cyclic oils (LIM, peppermint and ION) with linear oil (IPM) and forklike oil (CCT) improves the drug solubility of the system.

388  Chapter 9 50 IPM-LIM CCT-LIM

45 40

SC (mg/g)

35 30 25 20 15 10 5 0 0

20

40 60 Water content (wt%)

80

100

Fig. 9.40 The solubilization capacity (SC) of indomethacin (mg drug/g microemulsion) as a function of water content along the dilution line N65 at 25°C in the system water/sucrose laurate/PEG-7 glyceryl cocoate/oil1/R (+)-limonene for isopropyl myristate (IPM) and caprylic-capric triglyceride (CCT) as oil2. The mixing ratios of sucrose laurate/PEG-7 glyceryl cocoate and oil1/R (+)-limonene equal unity.

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