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1. PRACTICE SCHOOL – PHARMACEUTICS
TITLE- FORMULATION AND EVALUVATION OF ORAL
RECONSTITUTABLE DRY SUSPENSION CONTAINING
VORICONAZOLE
1
Submitted to-
Dr. Satheesha Babu
Assoc professor
Government college of pharmacy
Bengaluru
Smt. Manjula B.P
Assoc professor
Government college of pharmacy
Bengaluru
Submitted by-
Aashaya Rao M
Abhishek Hunchyalamath
Akhilesh
Akshata Jadav
Amareshwar
Ambhruni J Mathad
Bhavana G K
Brunda N
2. INTRODUCTION
Voriconazole, sold under the brand name Vfend among others, is an antifungal
medication used to treat a number of fungal infections. It is also used to treat
yeast infections.
This includes Aspergillosis, Candidiasis, Coccidioidomycosis, Histoplasmosis,
and infections by Scedosporium or Fusarium. It can be taken by mouth or used
by injection into a vein.
It is in the triazole family of medications. It works by affecting fungal
metabolism and fungal cell membranes. It is a broad spectrum antibiotic.
Available in both oral and intravenous form. The bioavailability of voriconazole
is around 96% and this allows the patients to be switched between oral and
intravenous administration.
2
3. 3
Adverse effects:
• Common side effects include vision problems, nausea, abdominal pain,
rash, headache, and seeing or hearing things that are not present. Use
during pregnancy may result in harm to the baby.
• Additionally, very common adverse effects, occurring in more than 10%
of people, include peripheral edema, headaches, trouble breathing,
diarrhea, vomiting, abdominal pain, nausea, rashes, and fever.
Contraindications
• It is toxic to the fetus; pregnant women should avoid using it.
• People who have hereditary intolerance for galactose, lactase deficiency,
or glucose-galactose malabsorption should not take this drug.
4. Preformulation studies-
1. Name of the drug- Voriconazole
2. Chemical name – (2R, 3S)-2-(2,4 Difluoro phenyl)-3-(S-Fluro
pyrimidin-4-yl)-1-(1,2,4-tri azole-1-yl) Butan-2-ol
3. Molecular formula- 𝐶16𝐻14𝐹3𝑁5𝑂
4. Molecular weight – 349.3105 g/mol
5. Appearance – white powder
6. Melting point – 133℃
7. Solubility - Voriconazole is soluble in Methanol, Ethanol,
Dichloromethane, Chloroform, Dimethyl sulfoxide.
8. Slightly soluble in water and phosphate buffer.
4
5. Melting point determination by capillary rise method-
Aim:
• To determine the melting point of voriconazole.
Materials Required:
• Voriconazole, capillary tube, thermometer, and Bunsen burner.
Procedure to determine the melting point of Voriconazole:
• Take a capillary tube and close its one end by heating the end in the flame for 2-3 minutes while
continuously rotating it.
• Take voriconazole powder on a tile.
• As shown in the figure below, firmly hold the closed end of the capillary tube between your finger and
thumb.
• Dip the open end of the capillary tube in the finely powdered voriconazole.
• Gently tap the capillary tube on the table to fill the compound in the capillary tube to about a length of
1–2 cm.
• Place the capillary tube and the thermometer in the melting point apparatus.
5
6. • Observe the capillary tube until the powder inside it melts.
• As soon as the powder melts remove the thermometer and check for the readings.
• This provides us with the melting point of the voriconazole drug.
Report –
Reference melting point of voriconazole as per IP 134℃.
Practical melting point of voriconazole 133℃.
6
7. Solubility-
• Take a pinch of voriconazole added into different organic solvents in a
beaker under a temperature of 40℃ and observe the solubility in
different solvents.
Report-
The solubility of voriconazole in different solvents are as follows:
Voriconazole is soluble in Methanol, Ethanol, Dichloromethane,
Chloroform, Dimethyl sulfoxide. Slightly soluble in water and phosphate
buffer.
7
9. • Standard curve for voriconazole-
The observation maxima of voriconazole were determined in PBS
(Phosphate buffer solution) pH- 6.8 using 1000mcg/ml concentration. The
solution was scanned from 400-200nm using a UV spectrophotometer.
• Preparation of calibration curve of VRC
A simple, fast, reproducible method was standardized for the estimation of
VRC, based on the solubility in the phosphate buffer 6.8.
• Preparation of primary stock solution:
100mg of accurately weighed VRC was dissolved in a 100ml, volumetric
flask and dissolved in 20ml methanol, the volume was made up with PBS
pH-6.8 to obtain a concentration of 1000mcg/ml.
9
10. • Preparation of secondary stock solution
25ml of primary stock was pipetted out into a 100ml volumetric flask. The volume was
made up with PBS pH 6.8 to obtain a concentration of 250mcg/ml.
• Preparation of working stock solution
From the secondary stock solution 0.5ml, 1ml, 1.5ml, 2.0ml, 2.5ml, 3.0ml, 3.5ml, 4ml and
4.5 ml were pipetted out into separate 25 ml volumetric flask and were diluted to the mark
with PBS pH-6.8 to obtain the concentration ranging from 5-45mcg/ml. These solutions
were scanned and the absorbance was measured at 256nm against the blank (PBS). The
absorbance values thus obtained were plotted against the respective concentrations to
obtain the standard calibration graph. The procedure was repeated 3 times and the average
values of absorbance were calculated. The data obtained were statistically evaluated to
obtain the standard deviation of the said values and the regression coefficient was
calculated. The linear regression analysis was done on the absorbance points. A straight line
equation (y=mx+c) was used to calculate the amount of drug.
10
12. Ingredient Role Qty(g)
Voriconazole API 1.2g
CMC Suspending
agent
0.9g
SSG Super
disintegrating
agent
0.3g
Sodium
benzoate
Preservative 0.06g
Sodium citrate Buffer 0.06g
Sucrose(qs) Sweetening
agent
18g
Tween 80 Surfactant 0.3g
KBr 0.006g
Aerosil Glidant 0.15g
Flavor of
pineapple
Flavoring agent qs
Color tartrazine Coloring agent qs
12
Formulation of dry granules containing voriconazole-
13. Experimental methodology-
Preparation of dried powder granule of voriconazole:
• The dose of suspension was selected 200mg/5ml as suspension
was meant to be prepared for pediatric patient.
• For pediatric patient the dose will be calculated on the basis of
weight of patient.
• For voriconazole the pediatric dose is 8mg/kg/day.
• Suspension of voriconazole was prepared using suspending agent,
wetting agent, preservatives, flocculating agent, buffer, anti-
caking agent, sweeteners, flavors of granulation technique.
• All the ingredients was passed through 60 or 80# before mixing.
13
14. • The solid ingredients were blended and mixed using water. The
granulation was carried out by means of wet granulation using
water as granulating fluid.
• The wet mass was formed into granules using 22 mesh size the
formed granules were dried on the oven and passed through 30
mesh after drying.
14
15. Evaluvation tests for the dried powder granules-
1. Bulk density –
The powder filled in measuring cylinder called as bulk volume of
powder and measure mass of the powder. Bulk density is ratio of
mass of powder to the bulk volume of the powder, it is a major use
to describe a packaging of powder.
BULK DENSITY =
𝑇𝑜𝑡𝑎𝑙 𝑤𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑝𝑜𝑤𝑑𝑒𝑟
𝑇𝑜𝑡𝑎𝑙 𝑣𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝑝𝑜𝑤𝑑𝑒𝑟
15
Trial no Weight of
powder
Volume of
powder(ml)
Bulk density
(g/ml)
Average bulk
density(g/ml
)
1 19.9 52 0.370
2 19.29 53 0.363 0.370
3 19.29 51 0.378
16. Tapped density
The pre-weighed powder was filled in measuring cylinder. Then it
was tapped manually. After 50 taps the volume is measured and the
tap density was measured using following formula:
TAPPED DENSITY =
𝑡𝑜𝑡𝑎𝑙 𝑤𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑝𝑜𝑤𝑑𝑒𝑟
𝑡𝑜𝑡𝑎𝑙 𝑣𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝑡𝑎𝑝𝑝𝑒𝑑 𝑝𝑜𝑤𝑑𝑒𝑟
16
Weight
of
powder
taken
Initial
volume
Taps
(g/ml)
50 100 150 200 250
19.29g 52ml 43 41 40 38 38
17. Carrs index-
Compressibility is indirectly related to the relative flow rate,
cohesiveness and particle size distribution of the powder. Powders
with compressibility values lesser than about 20%, has been found
to exhibit good flow properties.
CARRS INDEX =
𝑇𝐴𝑃𝑃𝐸𝐷 𝐷𝐸𝑁𝑆𝐼𝑇𝑌−𝐵𝑈𝐿𝐾 𝐷𝐸𝑁𝑆𝐼𝑇𝑌
𝑇𝐴𝑃𝑃𝐸𝐷 𝐷𝐸𝑁𝑆𝐼𝑇𝑌
× 100
17
Trial no. Percentage (%)
1 27.02
18. Hausner’s ratio:
The Hausner’s ratio expressed as the tap density divided by the bulk
density.
It is used to indicate the flowability of granular powders.
It is expressed as-
Hr = ρtap/ρb
18
Sl no. Tapped density Bulk density Hausner’s ratio
1 0.507 0.378 1.3412
19. Angle of repose-
It is the steepest angle of descent or dip relative to the horizontal plane to which the
material can be piled without slumping.
The maximum possible angle formed between the surface of the pile of powder and
horizontal surface.
θ =tan-1(h/r)
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Trial
no.
Diamete
r
Averag
e
Radiu
s
(cm)
Height
(cm)
h/r 𝜽
(in
degree
)
𝑑1 𝑑2 𝑑3 𝑑4
1 8.8 8.4 8.5 9 8.675 4.33 2.5 0.5773 29.93
2 8.8 8.7 8.8 8.8 8.775 4.38 2.4 0.5479 28.67
3 8.6 8.9 8.9 8.3 8.4 4.2 2.3 0.5476 28.67
22. 22
REMARK-
Angle of repose = 29.10° = Excellent
Carrs index = 23.02° = Passable
Hausner’s ratio=1.3412 = Passable
23. RECONSTITUTION OF DRY POWDER GRANULES INTO
SUSPENSION-
• 10g of final dried powder granules of voriconazole were diluted
upto 30 ml for final formulation.
23
24. Evaluvation of suspension of voriconazole-
• pH: The pH of the reconstituted suspension was determined
using pH meter. A glass rod was dipped into a suspension
containing 100mg of drug filled in a 50ml of the beaker. The
reconstituted suspension has a pH of 4 which is satisfactory for
the stability of voriconazole and maintains antimicrobial action
• Sedimentation Volume ratio: To study sedimentation of our
suspension, the sedimentation volume was determined as a
function of time. The sedimentation volume F was defined as the
ratio of final equilibrium volume of the sediment 𝑉𝑈 to the total
volume
𝑉0, before settling, as expressed in the following equation
F=
𝑽𝑼
𝑽𝟎
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25. In this study, the suspension was decanted in a cylinder of 100 ml
with diameter of 2.5 cm after 1 hour, 24 hour, 1 week the
sedimentation value F was determined.
25
Days F
𝑉0 𝑉𝑈 F
0 30 30 1
1 30 30 1
2 30 30 1
3 30 30 1
4 30 30 1
5 30 29 0.96
27. 1 1 1 1 1
0
0.2
0.4
0.6
0.8
1
1.2
0 1 2 3 4 5
F4
Sedimentation volume of suspension with drug
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28. Redispersibiltiy
For oral suspension which settle on storage ( produce sediment),
acceptance criteria for redispersibility maybe appropriate shaking (
mechanical or manual ) should be indicated. The time required to
achieve resuspension by the indicated procedure should be clearly
defined.
Reconstitution time
Acceptance criteria for reconstitution time should be provided for
drug powder products which require reconstitution. The choice of
diluent should be justified. Data generated during product
development maybe sufficient to justify skip lot of testing or
elimination of this attribute from the specification maybe proposed.
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30. Report-
The oral suspension of voriconazole for paediatric patient was
prepared, evaluated and submitted.
30
31. FORMULATION AND EVALUVATION OF FILM FORMING SPRAY
CONTAINING VORICONAZOLE
INTRODUCTION
• FILM FORMING FORMULATION REPRESENT A NOVEL FORM OF
SUSTAINED RELEASE TOPICAL PRODUCTS.
• THEY ARE APPLIED TO SKIN AS A LIQUID OR SEMI SOLID PREPARATION.
• BY EVAPORATION OF VOLATILE SOLVENT ON SKIN, THE POLYMER
CONTAINED IN FORMULATION FORM A SOLID FILM.
• PENETRATION AND PERMEATION STUDIES OF THE FORMULATION
INDICATE POTENTIAL UTILITY AS TRANS DERMAL THERAPEUTIC
SYSTEMS.
• THEY CAN BE USED AS AN ALTERNATIVE TO PATCH SYSTEM TO
ADMINISTERED A VARIETY OF DRUGS IN A TOPICAL WAY.
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32. Transdermal Transport :
• Penetration into the stratum corneum is limiting factor for amount of drug that can be
absorbed.
• Drugs can pass through stratum corneum by trans epidermal, trans follicular or trans
glandular routes.
• Depending on drug and formulation they penetrate the skin to different depths as shown in
figure.
• The condition of skin i.e., the skin area and the condition of skin barrier also influence
penetration.
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33. EXCIPIENTS:
1. Eudragit® L-100:
• It is commonly used polymer in a coating layer of modified release drug formulation.
• It prevent the drug release in the stomach.
• The amount of the Eudragit®L-100 in formula determines the dissolution profile of drug.
2. Ethyl cellulose-FILM FORMER
• Ethyl cellulose dissolved at 70ºC in either ethanol or ethyl acetate, the obtained solution
was set to cooled down to 6ºC to form a film.
3. Menthol-Penetration enhancer
• It increase the diffusion coefficient and effective concentration of drug in vehicle
improving partitioning between skin and formulation.
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34. • Decrease the thickness of the skin.
• This works better with cosolvents.
4. Polyethylene glycol:
• It have a role in increasing the permeation of antifungal drugs.
• It also act as solubilizer which is also useful in carrying drugs through the skin.
5. Tartrazine: colouring agent
• Tartrazine is a bright yellow azo dye that is more stable and cheaper alternative to natural
food dyes.
6. Ethanol: cosolvent
• It enhances the solubility of the drug in the dosage form.
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36. METHODOLOGY–
Prepare 50ml of film forming solution of Voriconazole:
• Dissolve eudragit L 100 (1.5g) and ethyl cellulose (0.5g) in ethanol
(30ml). Stir well for 1 hour in sonicator. (Solution: A)
• Dissolve menthol in few ml of alcohol (ethanol 5ml) (Solution: B)
• Dissolve tartrazine (0.025g) in 5ml of ethanol. (Solution: C)
• Add B and C solution into solution A and mix thoroughly.
• Stored in a spraying bottle.
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37. EVALUATION PARAMETERS
1. Appearance and film formation:
• The spray formulations had good clarity and were free from interfering particles.
• The dried film formed on the petri-dish after spraying was transparent and uniform.
• No precipitation was observed after film formation.
2. Viscosity:
• The viscosity of the formulation was measured using Ostwalds viscometer and viscosity
of all the formulation was found to be in the range of 27-53cps.
3. Evaporation time:
• Formulation was sprayed on ethyl alcohol sensitive paper/ filter paper and the drying
time or evaporation time was noted.
• The evaporation time was found to be between 3 to 7 min, which was well in desired
range for an ideal film-forming spray formulation.
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38. 4. Spray angle:
• The spray angle was determined using the pigmentation technique
of a spray-on slip of paper. Sudan red (10 mg) was solubilized in
the formulation to aid visual representation, and the sprays were
actuated horizontally on white paper mounted 15 cm from the
nozzle. The spray angle was calculated using the formula below.
Spray angle (θ) =tan−1 𝑙
𝑟
• Where, l is the spacing between the nozzle and the sheet, and r is
the mean radius of the circle
• The spray angle of prepared formulations was found between 25
to 30 degrees depicting its uniform delivery on the surface of the
skin.
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39. 5. Drug content:
• 1 ml of the prepared formulation was derived in phosphate buffer pH 7.4 for
4 hour at 100 rpm. The samples were then filtered and appropriately diluted.
The resulting mixture was further sonicated, and absorbance was recorded
spectrophotometrically at λmax.
• The solution was analyzed for drug concentration spectrophotometrically
at λmax of 256nm, for which formulation reported the highest drug
content.
39
41. 6. Film flexibility:
• The film was stretched in two to three directions after the film-forming Spray was sprayed on a petri-
dish. If the film ruptures, it is rated as a non-flexible film, and if it doesn’t, then it is rated as flexible.
• The flexibility and rupturing of formed films were observed.
7. Stickiness of the film:
• After the film was formed, a small ball of cotton wool was taken and pressed against the dried film
with slight pressure, and the film was visually inspected for fibers attached. The more the number of
fibers that get adhered to the film, the more “sticky” the film is.
• The stickiness was considered “medium” when a thin layer of cotton fibers adhered to the film. And
the film is said to be “non-sticky” if no fibers have adhered to the film
41
42. 8. pH:
• The pH value of resulting spray solution was recorded with a digital pH meter.
• The pH of the solution was in the range of 5.5 to 6.5 which lies in the normal
pH range of skin and would not cause any kind of skin irritation.
9. Washability:
• After drying, the washability of the film was checked with water, and it was
rated as Good (+++), Moderate(++), and Poor (+).
42
43. 10. Leak test:
• The containers filled with solutions under test were arranged in an
upright position at 30°C for 6 hours as a part of the leak test. The
bottles were balanced, and weight was recorded before and after the test
stage. The variation in the weight of the bottle was written down to
anticipate leakage percentage.
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46. CONCLUSION:
• In the present study, an attempt was made to formulate and characterize a film-forming
spray. Various polymers were used in different concentrations to form a uniform film after
the solution was sprayed.
• Prepared formulations were analyzed for various evaluation parameters, including
evaporation time, spray angle, spray pattern, volume actuated and drug content.
• Results concluded that formulation exhibited good physical properties.
• Thus, on the accounts of results of evaluative studies, it can be concluded that the prepared
film forming spray formulation can be a promising approach for the treatment of
superficial fungal infections.
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