Solid Dispersion Characteristics of Whiteleg Shrimp (Litopenaeus vannamei) Extracted Chitosan with HPMC and PVP K-30 as

Anti-cholesterol Agents

 

Hilya N. Imtihani*, Silfiana N. Permatasari, Fitria A. Thalib

Surabaya Pharmacy Academy, Surabaya, 60232, Indonesia.

 

ABSTRACT:

This study aims at evaluating the characteristics of chitosan solid dispersion from whiteleg shrimp (Litopenaeus vannamei). As anti-cholesterol agent, chitosan requires solubility enhancement which can be facilitated in solid dispersion. Here, chitosan solid dispersion was made by solvent evaporation technique used HPMC and PVP K-30 as the carriers, in which the chitosan was prepared from whitleg shrimp shell Chitosan solid dispersion was varied into six formulation, i.e. chitosan: HPMC = FH1 (1:0.25), FH2 (1:0,5), FH3 (1:2), and chitosan: PVP K-30 = FP1 (1:1), FP2 (1:2), and FP3 (1:3), and pristine chitosan, HPMC, and PVP K-30 were utilized as reference compound. Characteristics of chitosan solid dispersion were assessed from the solubility test, SEM, XRD, and FTIR. The result indicates that solubility of chitosan solid dispersion was better than the pristine chitosan. The recommended formula from this study was FP3, because obtained smaller particle size than the other, that could increase the solubility of chitosan. The crystallinity of chitosan remained unchanged upon solid dispersion preparation.

 

 

 

INTRODUCTION:

Shrimp shell contains 20-40% of protein, 20-50% calcium and also magnesium carbonate, and 15-40% chitin and this composition depends on the shrimp’s species¹. Chemically, chitin is a water-insoluble polymer ((1,4) -2-acetamide-2-deoxy-D-glucose) that cannot be digested by mammals. Nonetheless, hydrolysis of chitin using a strong base (deacetylation process) into chitosan can improve its chemical properties². Chitosan have non-toxic, biocompatible, biodegradable characteristics and able to form complex compounds, such as with cholesterol³.

 

Chitosan, that is poly-D-glucosamine-((1, 4)-2-amino-deoxy-D-glucose), shows a yellowish-white amorphous solid with a fixed crystal structure from the initial form of pristine chitin⁴.

 

Chitin is obtained from shrimp shells through several stages, including deproteination (separation of proteins), demineralization (removal of minerals). Meanwhile, chitosan is obtained upon deacetylation (removal of acetyl groups)⁴. For further application, chitosan shall be evaluated which includes the organoleptic test, yield test, ninhydrin test, and deacetylation degree test to ensure the quality of the chitosan produced^5,6.

 

Chitosan consume has been reported to decrease serum total cholesterol levels by 5,8-42,6% and LDL (low-density lipoprotein) levels circa 15.1-35.1%⁷. It is found that giving 30 chitosan tablets (45 mg of chitosan/tablet) with the rule of three times a day can reduce cholesterol levels⁸. Therefore, chitosan can be used as an anti-cholesterol drug ingredient. However, chitosan has also poor solubility in water, strong alkaline solutions, sulfuric acid, organic solvents such as alcohol, acetone, dimethylformamide, and dimethylsulfoxide. Chitosan is known slightly soluble in hydrochloric acid (HCl) and nitric acid (HNO₃), but chitosan is soluble in 1% -2% of acetic acid, and readily dissolves in 0.2-1.0% methanoic acid. To enable its bioactivity as anti-cholesterol drug, efforts shall be taken to increase the solubility, for instance by formulating into solid dispersion system⁹. Chitosan can also produce from shell of crab Paratelphusa hydrodromous that have antibacterial activity¹⁰, and uses as a adsorbent from some heavy metal like zinc, iron, etc¹¹.

 

In developing drug formulations, to increase the rate of dissolution, bioavailability, and low solubility, it can be done by reducing the particle size and hence, increasing surface area enhance the solubility of a drug. Bioavailability of drug including orally administered drug mainly depends on its solubility and permeability. Various methods can be used to increase the drug solubility, one of which is a solid dispersion method that employs a water-soluble carrier so that it increases the drug solubility and dissolution. Strategies for enhance solubility in solid dispersion are fusion, solvent evaporation etc and the novel strategy is hot melt extrusion (HME)¹². Solid dispersion with other strategies like grinding method evidently give better dissolution than the pure drug¹³. In general, solid dispersions consist of a matrix which have hydrophilic property and a hydrophobic medicinal compound. Matrix that used can be crystalline or amorphous which can be molecularly dispersed¹⁴. Among the carriers used in solid dispersion formulation, HPMC and PVP K-30 are considered the extensively used since these polymers are hydrophilic with excellent water solubility and can be further used as stabilizers¹⁵. PVP K-30 is a hydrophilic carriers that can enhance the solubility and dissolution from poorly water soluble drugs like nebivolol in solid dispersion system by solvent evaporation method¹⁶. Both of PVP K-30 and HPMC can increase the solubility from Raloxifene HCl and the maximum solubility showed by PVP K-30¹⁷.

 

In this study, we have investigated the characteristics of chitosan-based solid dispersion with different carriers and drug to carrier ratio. In addition, we prepared the chitosan using white leg shrimp shells. The characterization includes qualitative solubility test, SEM, XRD, and FTIR. We compare the solid dispersion characters with the raw materials, that is chitosan, HPMC, and PVP K-30. The characterization enables the evaluation of solid dispersion, improving solubility, dissolution, and bioavailability of the chitosan. Increase solubility and dissolution will improve bioavailability^18,19.

 

MATERIAL AND METHODS:

Chemicals and reagents:

Materials used in this work were whiteleg shrimp (Litopenaeus vannamei) collected from local market, HCl (Mercks®, pharmaceutical grade), NaOH (Mercks®, pharmaceutical grade), ninhidrine solution, Aquades (Brataco®, pharmaceutical grade), Alcohol 90% (pharmaceutical grade), HPMC (pharmaceutical grade), PVP K-30 (pharmaceutical grade), Magnesium Stearate (analytical grade), Talk (analytical grade) and Avicel PH 102 (analytical grade).

 

Instrumentation:

All characterization performed in this work used the following instruments: Thermo UV-visible spectrophotometer, Laqua Horiba pH meter, Scanning Electron Microscopy (SEM, FEI Inspect-S50) operated at a 20.0kV acceleration voltage, FTIR (Fourier-transform infrared spectrometer) (Thermo Scientific Nicolet iS10), X-ray diffractometer (XRD, X-pert MPD).

 

Chitosan Synthesis:

Pre-treatment:

The shell of whiteleg shrimp (Litopenaeus vannamei) was washed with running water. The clean shell was boiled for 15 minutes and dried. The dried shell was then grounded and sieved with a 100 mesh²⁰.

 

Demineralization:

For demineralization, 100g shell powder was soaked into 1M HCl solution and stirred at 200rpm at 75ºC for 1 hour. The mixed solution was then filtered, rinsed with distilled water (aquadest) until neutral pH was achieved. The filtered sample was then dried in oven at 60ºC for 24 h⁴.

 

Deproteination:

The dry solids from demineralized one was dissolved in 3.5% NaOH and stirred at 450rpm at 65ºC for 2 h. The mixed solution was filtered and rinsed with distilled water until neutral pH was achieved. The filtered sample was then dried in oven at 60ºC for 24 h to obtain chitin²⁰.

 

Deacetylation:

The obtained chitin was dissolved in 60% NaOH solution by ratio of 1:20 (w/v) and stirred at 250rpm at 100ºC for 4 h. The solution was then filtered, rinsed thoroughly, and dried in the oven to yield chitosan.

 

Chitosan Evaluation:

Deacetylation degrees:

The degree of deacetylation is a parameter that determines the quality of chitosan, where this value shows the proportion of acetyl groups that can be removed from the yield of chitin and chitosan. The higher the deacetylation degree of chitosan, the lower the acetyl group found in chitosan²¹. The degree of deacetylation of chitosan is determined by several factors, that is, the deposition of NaOH used, temperature, and duration of the deacetylation process²². The standard percent of the deacetylation degree is 70-95%²³. The degree of deacetylation is determined by using FTIR spectroscopy and evaluating the spectrum in the frequency range of 1000-4000 cm^-1. The degree of deacetylation (DD) value of chitosan is estimated according to the Baxter’s equation²⁴:

 

 Where A₁₆₅₅ is the absorbance at 1655 cm^-1 attributed to the amide-I band and A₃₄₅₀ is the absorbance at 3450cm^-1 assigned to the hydroxyl band.

 

Organoleptic test:

Organoleptic test of chitosan was included evaluation of the shape and color of the chitosan. Typically, chitosan shows flaky powders and is light brown to white²⁵.

 

Yield value:

The yield of chitosan was determined from the weight of chitosan produced compared to the weight of raw material for shrimp shells²⁶. The formula for calculating the % yield value was estimated using following equation:

 

                                   The weight of chitosan produced

Yield value (%) =--------------------------------------------× 100%

                                        Shrimp shell weight

 

Ninhydrin test:

The ninhydrin test was used to show the presence or absence of an amine group in chitosan. The presence of amine groups in the chitosan sample was indicated by color change into purple⁷.

 

Solid Dispersion Preparation:

Chitosan-based solid dispersion was prepared in three different ratios (w/w) using HPMC and PVP K-30. The ratio of chitosan and the carriers was summarized in Table 1. To prepare solid dispersion, chitosan was dissolved and stirred in 2% acetic acid (1:50). For drug carriers, HPMC and PVP-K30 were dissolved in ethanol 90% (1:5) and 2% acetic acid (1:5), respectively. Afterwards, the chitosan solution was mixed with either HPMC or PVP K-30 solution following the formula (Table 1) and evaporated in water bath at 50-60ºC until a precipitate was formed. The resulting precipitates was then dried in the oven at 50ºC for 2 h. Eventually, the dried dispersion was pounded and sifted using 100 mesh sieves²⁷.

 

Table 1: Ratio of drug to carrier for solid dispersion formulation

Formula	Chitosan	HPMC	PVP K-30
FH1	1	0.25	-
FH2	1	0.5	-
FH3	1	2	-
FP1	1	-	1
FP2	1	-	2
FP3	1	-	3

 

Characterization of solid dispersion:

Solubility Test:

The visual inspection of solubility was carried out by dissolving 100mg of the solid dispersion in 1ml of distilled water. This test was carried out in triplicate.

 

Scanning Electron Microscopy (SEM):

Micromorphology of pristine chitosan as well as chitosan-based solid dispersion were analyzed using the Scanning Electron Microscopy (SEM, FEI Inspect-S50) operated at a 20.0 kV acceleration voltage²⁸.

 

Fourier Transform Infrared (FTIR) spectroscopy:

FTIR spectra were obtained using Thermo Scientific Nicolet iS10 within the range of 500-4000 cm^-1 and samples were prepared in KBr disks in a hydrostatic press²⁹.

 

X-ray diffraction (XRD)

The microstructural properties of the sixth formulas, i.e. PVP K-30, HPMC, and chitosan, chitosan/PVP-K30, chitosan/HPMC, were evaluated by using XRD (PANalytical X-pert MPD). The diffractometer was operated at 40kV and 20mA and the samples were irradiated using a Cu-Kα radiation sources²⁹.

 

RESULTS AND DISCUSSION:

Chitosan prepared from the whiteleg shrimp (Litopenaeus vannamei) shells show characteristics as follow (Table 2):

 

Table 2: Evaluation of chitosan properties

Deacetylation degree	Organoleptic	Yield value	Ninhydrin
99.33%	White powder	16,21%	+ purple

 

The standard deacetylation degree is within the range of 70-95%²³. Here, our preparation yields chitosan with deacetylation degree of 99.33% which is already high. The organoleptic tests indicate that the resultant chitosan powder is white and fine. The synthetic yield is found 16, 21% which is considerably low probably due to mass loss during rigorous washing process. The ninhydrin test further confirms that the sample is indeed chitosan as the amine group from the chitosan alters the color into purple^18,19.

 

The first evaluation of solid dispersion is based on the visual solubility test. The results of the solubility test show that the solid dispersion is more homogeneously soluble in distilled water compared to the pristine chitosan. The chitosan forms sedimentation upon dissolving in water while the solid dispersions form a homogeneous gel. The results of the solubility test are shown in Figure 1. Hydrophilic carrier like PVP K-30 and HPMC can increase in drug wettability, conversion to amorphous form and solubilization of the drug. A water insoluble drug made to solid dispersion and by the in vitro dissolution test showed a significant increase in the dissolution rate of solid dispersion as compared with the pristine drug³⁰.

 

Fig. 1: Visual inspection from the solubility test from different chitosan-based solid dispersions.

 

Morphology of the chitosan and the solid dispersions is evaluated from the corresponding SEM images (Figure 2 and Figure 3). The solid dispersion was evaluating with SEM, showing fine needles, with smooth surface, that partially agglomerated³¹. For pristine chitosan, the average size is ca. 0.308mm (Figure 2B) with irregular thin-flake form. Upon formulation into chitosan/HPMC solid dispersion, it shows that the chitosan particles coalesce with the HPMC as a carrier yielding more irregular flakes. Interestingly, the solid dispersion of chitosan/PVP K-30 shows more homogeneous dispersion indicating that the chitosan molecules are dispersed uniformly in carrier matrices. Particle size of solid dispersion with PVP K-30 in 1:3 ratio (FP3) show more small than with HPMC. The solid dispersion with PVP K-30 also shows rock-like particles. Overall, the SEM studies indicate that no significant changes in the chitosan and solid dispersion morphology. The particle size distribution of FH1-FP3 are shown in Figure 4. The average particle size of chitosan-based solid dispersions span between 0.20 – 0.27mm which is smaller than that of pristine chitosan. This smaller particle leads to the increasing solubility of chitosan because increasing the surface area of the particles³². From the particle size measurement, FP3 have the smaller particle size than the others, that is 0,194mm. It can take effect to the solubility of chitosan and increase bioavailability. Reduction of particle size from solid dispersion indicating that amorphous particle formed³¹. and amorphization of a drug can also enhanced the solubility and dissolution rate³³. This can be the reason for increasing solubility of chitosan after made solid dispersion.

 

Fig. 2: (A) SEM image of Chitosan from Litopenaeus vannamei and (B) the particle size distribution of chitosan.

 

Fig. 3: SEM images of different solid dispersions: (A) FH1, (B) FH2, (C) FH3, (D) FP1, (E) FP2, and (F) FP3. The scale bare is equal to 1 mm.

 

Fig. 4: Distribution pictures of different solid dispersions: (F1) FH1, (F2) FH2, (F3) FH3, (F4) FP1, (F5) FP2, and (F6) FP3

 

Figure 5 displays the FTIR spectrum of chitosan solid dispersion, chitosan, HPMC, and PVP K-30. The solid dispersion chitosan and HPMC as carrier shows broadening of the OH group peak while in the chitosan/PVP-K30 solid dispersion chitosan the peak is shifted toward higher wave number 3381.08cm^-1 (FP2) which may be due to the presence of more number of N-H groups in PVP K-30. Similar behavior is observed for C-N group vibration that is shifted toward higher wave number 1288.85 cm^-1 (FP1) which can be due to the presence of more C-N groups in PVP K-30. The vibrational band of C=O groups in PVP K-30 also appears in the solid dispersion of PVP K-30 in ~ 1644.74 cm^-1. However, other peaks associated to OH, C-H, C=C, C-O stretching remain unchanged. This indicates that the molecule might not be significantly changed and there is no interaction and degradation between the chitosan and carrier as the solid dispersion is only the dispersion of one or more active ingredient in a carrier or matrix at solid state^30,34,35 (Table 3).

 

Table 3: Comparison of IR values of pristine drug with solid dispersion

Functional groups	Wave number (cm-1)
	Range	Chitosan	FH1	FH2	FH3	FP1	FP2	FP3
OH	3500-3300	3495.26	3495.26	3495.26	3495.26	3495.26	3495.26	3495.26
N-H	3350-3180	3291.79	3247.21	3259.98	3361.3	3257.54	3381.08	3369.72
C-H	3000-2800	2872.66	2872.74	2880.38	2888.48	2925.45	2922.67	2950.83
C=C	1600-1475	1559.47	1539.77	1541.17	1545.14	1544.78	1559.59	1559.63
C-N	1350-1000	1149.01	1150.44	1405.91	1406.32	1288.85	1288.01	1287.94
C-O	1300-1000	1023.43	1016.48	1019.09	1019.18	1018.95	1069.12	1069.3

 

The X-ray diffraction of the solid dispersion system and the initial material can be seen in the Figure 6. The X-ray diffraction pattern of chitosan reveals a sharp and intense peak indicating higher crystallinity of the drug. The identified diffraction peaks (2θ) are observed at 9.05. 18.79, 29.24, dan 39.04. More carriers in the solid dispersion can coating the crystal lattice of drugs, because there was residual carrier from solvent evaporation method, and this make the drug diffractogram decrease by increasing carriers. That was happened in the mixture of carriers with small amount of low MW (molecular weight) drugs³⁶. It showed in the Fig.6 that diffractogram of chitosan decrease in FH3. Furthermore, the X-ray diffraction pattern of the solid dispersions is found as a superposition of the diffraction pattern of the drug and carriers. Therefore, there is no amorphization of the chitosan during solid dispersion preparation. In brief, SEM and IR studies corroborate the evaluation of solid dispersion using X-ray diffractometry that no interaction between chitosan and the carriers.

 

 

Fig. 5: FTIR spectra of various solid dispersions, the sole carriers, and pristine chitosan.

 

Fig. 6: X-ray diffractograms of solid dispersions, carriers, and chitosan.

 

CONCLUSION:

Chitosan prepared from the whiteleg shrimp (Litopenaeus vannamei) shells yield a product that satisfy the standard properties of chitosan. The solubility from the visual test shows better solubility of the solid dispersion compared to the pristine chitosan. FP3 have the smaller particle size that can increase the chitosan bioavailability. Characteristics of chitosan solid dispersion were assessed from the SEM, XRD, and FTIR. The characterization results show that the solid dispersions do not significantly affect the crystallinity of chitosan as there is no amorphization observed.

 

ACKNOWLEDGEMENT:

The authors would like to thank for financial support from LLDIKTI Wilayah VII Kementerian Pendidikan dan Kebudayaan for research grants “Penelitian Dosen Pemula” agreement No. 083/SP2H/LT/DRPM/2020 tanggal 9 Maret 2020; 145/SP2H/LT-MONO/LL7/2020 tanggal 17 Maret 2020; 061/AKFAR-SBY/LPPM/70.03/ III/2020 tanggal 30 Maret 2020 and thank for all facilities from Akademi Farmasi Surabaya.

 

CONFLICT OF INTEREST:

The authors declare that have no conflict of interest.

 

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Received on 17.09.2020           Modified on 24.10.2020

Accepted on 16.11.2020         © RJPT All right reserved