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G. PARTICLE SIZE DISTRIBUTION FOR NASAL SUSPENSIONS

G. PARTICLE SIZE DISTRIBUTION FOR NASAL SUSPENSIONS

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58



Handbook of Pharmaceutical Formulations: Liquid Products



Excipients offer several possibilities and mechanisms. For

microemulsions, Cremophor RH 40, Cremophor EL, and

Solutol HS 15 act as surface active solubilizers in water

and form the structures of micelles. The micelle that envelops the active substance is so small that it is invisible, or

perhaps visible in the form of opalescence. Typical fields

of application are oil-soluble vitamins, antimycotics of the

miconazole type, mouth disinfectants (e.g., hexiditin), and

etherian oils or fragrances. Solutol HS 15 is recommended

for parenteral use of this solubilizing system and has been

specially developed for this purpose.



XV. COMPLEXING

The soluble Kollidon products form reversible complexes

with many hydrophobic active substances, and clear solutions in water are thus obtained. This may be affected by

the molecular weight. The longer the chains or the higher

the K-value of the Kollidon type are, the stronger the

solubility effect is, and thus the greater the solubility that

can be obtained by the active substance. In practice, this

effect was mostly exploited for the solubilization of antibiotics in human and veterinary medicine. There are also

restrictions on the use of this substance in human parenterals. In many countries the K-value must not exceed 18,

and there is also a restriction on the amount to be used

for each dose administered in intramuscular application.



XVI. HYDROPHILIZATION

Active substances can also be solubilized by Lutrol F 68

in addition to the Cremophor and Kollidon products. The



© 2004 by CRC Press LLC



mechanism is probably based, for the most part, on the

principle of hydrophilization. Micelle formation is certainly of minor significance, if it exists at all.



XVII. STABILIZING SUSPENSIONS

Various BASF pharmaceutical excipients with different

functions can be used for stabilizing suspensions. The

following groups of products can be offered for stabilizing

oral and topical suspensions. Soluble Kollidon products

can be used at low concentrations; that is, at 2 to 5%,

Kollidon 90 F suffices to stabilize aqueous suspensions.

A combination consisting of 2% Kollidon 90 F and 5 to

9% Kollidon CL-M has proved to be an effective system

for stabilizing suspensions. Kollidon 30 is also used for

this purpose. It can be combined with all conventional

suspension stabilizers (thickeners, surfactants, etc.). The

use of Kollidon CL-M as a suspension stabilizer has nothing whatever to do with the principle of increasing the

viscosity. The addition of 5 to 9% Kollidon CL-M has

practically no effect in changing the viscosity, but it

strongly reduces the rate of sedimentation and facilitates

the redispersability, in particular — an effect that is consistent with the low viscosity. One of the reasons for this

Kollidon CL-M effect is its low (bulk) density, which is

only half of that of conventional crospovidone (e.g., Kollidon CL). The polyoxamers, Lutrol F 68 and Lutrol F

127, in concentrations of 2 to 5%, expressed in terms of

the final weight of the suspension, offer a further opportunity of stabilizing suspensions. They also do not increase

viscosity when used in these amounts and can be combined with all other conventional suspension stabilizers.



Part II

Manufacturing Formulations



© 2004 by CRC Press LLC



Manufacturing Formulations



61



Abacavir Sulfate Oral Solution

Ziagen oral solution is for oral administration. One milliliter (1 mL) of Ziagen oral solution contains abacavir

sulfate equivalent to 20 mg of abacavir (20 mg/mL) in an

aqueous solution and the inactive ingredients artificial

Bill of Materials

Scale (mg/mL)

20.00

344.40

0.30

2.00

2.00

q.s.

q.s.

1.50

0.18

50.00

q.s.

q.s.



Item

1

2

3

4

5

6

7

8

9

10

11

12



strawberry and banana flavors, citric acid (anhydrous),

methylparaben and propylparaben (added as preservatives), propylene glycol, saccharin sodium, sodium citrate

(dihydrate), and sorbitol solution.



Material Name

Abacavir, use abacavir hemisulfate

Sorbitol 70%

Sodium saccharin

Strawberry flavor

Banana flavor

Sodium citrate dihydrate for pH adjustment

Citric acid anhydrous for pH adjustment

Methyl paraben

Propyl paraben

Propylene glycol

Hydrochlorie acid dilute for pH adjustment to 4.0

Sodium hydroxide for pH adjustment



MANUFACTURING DIRECTIONS

1. The pH range for this solution is from 3.8 to 4.5.

2. Charge 40% of the propylene glycol to an

appropriately sized stainless steel and add

methylparaben and propylparaben with mixing,

and mix until dissolved.

3. Charge purified water into a stainless steel manufacturing tank equipped with a suitable mixer

to approximately 40% of final batch volume.

4. Add sorbitol solution to the manufacturing

tank.

5. While mixing, add item 1 and mix until dissolved.



Quantity/L (g)

23.40

344.40

0.30

2.00

2.00

10.00

7.00

1.50

0.18

50.00

q.s.

q.s.



6. While continuing to mix the solution, the paraben/glycol solution, the remaining propylene

glycol, artificial strawberry flavor, artificial

banana flavor, saccharin sodium, citric acid

anhydrous, and sodium citrate dihydrate are

added and mixed until dissolved.

7. Turn off the mixer and bring the solution to a

volume of 500 L, and mix until a homogeneous

solution is achieved.

8. Measure and adjust pH to 3.8 to 4.5 with

sodium hydroxide or hydrochloric acid.

9. Filter the solution through a clarifying filter into

an appropriately sized receiving vessel.



Acetaminophen Rectal Solution

Bill of Materials

Scale (mg/mL)

Item

q.s.

1

50.00



2



Material Name

Vehicle (Pluronic P105 44.21%, propylene

glycol 52.635, water 3.16%)

Acetaminophen micronized



MANUFACTURING DIRECTIONS

1. Mill and screen the acetaminophen to further

reduce the particle size.



© 2004 by CRC Press LLC



Quantity/L (g)

q.s. to 1 L

50.00



2. Add the acetaminophen into a clean vessel.

3. Add propylene glycol to the vessel.

4. Subsequently add the poloxamer and water to

the vessel. Mix until uniform.



62



Handbook of Pharmaceutical Formulations: Liquid Products



Acetaminophen Drops

Bill of Materials

Scale (mg/mL)

739.0

90.0

17.5

8.75

0.05

2.5

2.0

65.0

q.s.

a



Item

1

2

3

4

5

6

7

8

9



Material Name

Propylene glycol

Acetaminophen

Saccharin sodium powder

Sodium chloride

Dye red FD&C No. 40a

Water purified

Flavor wild cherry artifical

Alcohol (ethanol) 190 proof nonbeverage

Water purified



Check for local regulatory allowance to use red dyes.



MANUFACTURING DIRECTIONS

Caution: Ensure that the solution in the tank never exceeds

65˚C.

1. Add 739 g propylene glycol to jacketed mixing

tank and start heating with slow mixing.

2. Dissolve dye in 2.5 mL purified water and add

to tank while mixing. Rinse container with

small amount of purified water and add to tank.

3. While mixing, add acetaminophen, saccharin

sodium, and sodium chloride.



© 2004 by CRC Press LLC



Quantity/L (g)

739.0

90.0

17.5

8.75

0.05

2.5

2.0

65.0

q.s. to 1 L



4. Hold at 60˚ to 65˚C with continued moderate

mixing until it is all in solution.

5. Force cool to less than 30˚C with slow mixing.

6. Blend flavor with alcohol and add to tank with

slow mixing.

7. Add purified water with mixing q.s. to make

1 L.

8. Mix well with moderate agitation until uniform.

9. Filter through 8-micron Millipore membrane

(or equivalent).



Manufacturing Formulations



63



Acetaminophen Oral Suspension

Bill of Materials

Scale (mg/5 mL)

250.00

2500.00

5.00

1.500

0.300

35.00

400.00

2000.00

10.00

0.500

22.500

3.500





Item

1

2

3

4

5

6

7

8

9

10

11

12

13



Material Name

Acetaminophen micronized, 2.0% excess

Sucrose

Methyl paraben

Propyl paraben

Sodium citrate

Glycerin (Glycerol)

Glycerin (Glycerol)

Sorbitol (70%)

Xanthan gum (Keltrol F)

Dye

Flavor

Strawberry flavor

Water, purified



MANUFACTURING DIRECTIONS

1. Acetaminophen dispersion should be uniformly mixed or levigated. If acetaminophen

dispersion is either added to hot syrup base or

homogenized for a long time, flocculation may

appear. While handling the syrup, mucilage, or

drug dispersion, the handling loss should not

be more than 1%. If the loss exceeds 1%, it

may give poor suspension.

2. Add 180 g of item 13 to the mixer and heat to

90˚C.

3. Dissolve items 3 and item 4 while mixing. Add

and dissolve item 2 while mixing. Cool down

to about 50˚ to 55˚C.

4. Add and dissolve item 5 while mixing. Filter

the syrup through T 1500 filters washed with

item 13. Collect the syrup in clean stainless

steel tank.

5. Disperse item 9 in item 6 in a separate stainless

steel container. Add 40 g of hot item 13 (90˚C)

at once while mixing. Mix for 20 minutes to

make a homogeneous smooth mucilage.

6. Mix item 7 in 10 g of item 13 (25˚C) in a

separate stainless steel container. Add item 1

while mixing with stirrer. Mix for 25 minutes

to make uniform suspension.



© 2004 by CRC Press LLC



Quantity/L (g)

51.00

500.00

1.00

0.30

0.06

7.00

80.00

400.00

2.00

0.10

4.50

0.70

q.s. to 1 L



7. Add sugar syrup and mucilage to the mixer.

Rinse the container of mucilage with 15 g of

item 13 and add the rinsings to the mixer. Cool

to 25˚C while mixing.

8. Add item 1 dispersion to the mixer. Rinse the

container of dispersion with 15 g of item 13

and add rinsings to the mixer. Check the suspension for uniformity of dispersion.

9. Mix for additional 5 minutes at 18 rpm, vacuum

0.5 bar if required.

10. Add item 8 to the mixer and mix for 10 minutes.

Dissolve item 10 in 7 g of item 13 and add to

the mixer.

11. Disperse item 11 in 7 g of item 13 and add to

the mixer. Add item 12 to the mixer.

12. Add cold item 13 (25˚C) to make up the volume

up to 1.0 L.

13. Homogenize for 5 minutes at low speed under

vacuum 0.5 bar, 18 rpm, temperature 25˚C.

14. Check the dispersion for uniformity.

15. Check the pH. Limit 5.7 ± 0.5 at 25˚C. If

required adjust the pH with 20% solution of

Citric Acid or Sodium Citrate.

16. Transfer the suspension through 630 micron

sieve after mixing for 5 minutes at 18-20 rpm,

temperature NMT 25˚C, to the stainless steel

storage tank.



64



Handbook of Pharmaceutical Formulations: Liquid Products



Acetaminophen Suspension

Bill of Materials

Scale (mg/10 mL)

500.00

50.00

50.00

500.00

10.00

3000.00

q.s.



Item

1

2

3

4

5

6

7



Material Name

Acetaminophen, powder

Citric acid, powder

Sodium citrate

Kollidon CL-M

Orange flavor

Dextrose

Water



MANUFACTURING DIRECTIONS

1. Prepare the solution of dextrose in water and

add the other solid ingredients with stirring in



Quantity/L (g)

50.0

5.0

5.00

50.0

1.00

300.0

589.0



the following sequence: citric acid, sodium citrate, orange flavor, Kollidon CL-M, and acetaminophen.

2. A white, homogeneous suspension is obtained.



Acetaminophen Syrup for Children

Bill of Materials

Scale (mg/mL)

25.00

300.00

60.00

40.00

q.s.

q.s.

q.s.



Item

1

2

3

4

5

6

7



Material Name

Acetaminophen, crystalline

Kollidon 25 or Kollidon 30

Glycerol

Sodium cyclamate

Orange flavor

Raspberry flavor

Water



MANUFACTURING DIRECTIONS

1. Dissolve Kollidon in water, add acetaminophen

and cyclamate, heat to 50˚C, and stir to obtain

a clear solution.



© 2004 by CRC Press LLC



Quantity/L (g)

25.00

300.00

600.00

40.00

<01.0

2.00

575.00



2. Dissolve the flavors and mix with glycerol. The

obtained syrup is a viscous, clear, sweet, and

only slightly bitter liquid.



Manufacturing Formulations



65



Acetaminophen Syrup

Bill of Materials

Scale (mg/mL)

50.0

50.0

40.0

1.00

200.0

150.0

200.0

310.0



Item

1

2

3

4

5

6

7

8



Material Name

Acetaminophen (Merck)

Sorbitol, crystalline

Cyclamate sodium

Strawberry flavor

Kollidon 25

Glycerol

1,2-Propylene glycol

Water



MANUFACTURING DIRECTIONS

1. Dissolve first Kollidon 25 and then the other

solid components in the solvent mixture of

glycerol, propylene glycol, and water.



© 2004 by CRC Press LLC



Quantity/L (g)

50.0

50.0

40.0

1.00

200.0

150.0

200.0

310.0



2. The result is a clear solution of certain viscosity

having only a slightly bitter taste. To prevent

discoloration during storage, 0.2 to 0.5% cysteine could be added as an antioxidant.



66



Handbook of Pharmaceutical Formulations: Liquid Products



Acetaminophen Syrup

Bill of Materials

Scale (mg/mL)

569.00

2.00

1.00

1.00

1.00

204.00

35.00

77.11

0.12

0.12

q.s.

q.s.



Item

1

2

3

4

5

6

7

8

9

10

11

12



Material Name

Sucrose (sugar granulated)

Sodium citrate dihydrate powder

Acid citric anhydrous powder

Saccharin sodium powder

Sodium chloride powder

Propylene glycol

Acetaminophen

Alcohol (ethanol) 190 proof

Flavor cherry artifical N59456/A

Dye red FD&C N40

Water purified

Filter aid hyflo



MANUFACTURING DIRECTIONS

1. Add 300 mL purified water to a jacketed stainless steel mixing tank. Start heating.

2. Add sugar with mixing.

3. Heat to 60˚– 65˚C and hold. Mix for complete

solution.

4. Add, while mixing, sodium citrate, citric acid,

sodium saccharine, and sodium chloride. Mix

for complete solution. Add propylene glycol by

mixing.

5. Add acetaminophen powder with moderate

mixing. Continue mixing at 60˚ – 65˚C for complete solution. Force cool to 25˚ – 30˚C with

slow mixing.



© 2004 by CRC Press LLC



Quantity/L (g)

560.0

2.0

1.0

1.0

1.0

204.0

35.0

77.112

0.12

0.10

400.0

q.s.



6. Blend cherry flavor with approximately twice

its volume of alcohol and add with mixing.

Rinse the container with several portions of

alcohol and add. Mix until uniform.

7. Dissolve red dye in approximately 4.0 g of

slightly warmed (50˚ – 60˚C) purified water and

add by mixing. Rinse the container twice with

approximately 1.5 g purified water and add to

step 6.

8. Mix until uniform. Adjust volume to 1 L with

purified water. Mix well.

9. Add a small amount of hyflo filter aid to the

mixing tank and continue to mix slowly while

filtering.

10. Filter through press until sparkling clear. Use

clarifying pad backed by lint-free filter paper.



Manufacturing Formulations



67



Acetaminophen, Chlorpheniramine, and Pseudoephedrine Syrup

Bill of Materials

Scale (mg/mL)

24.00

3.00

0.44

14.00

2.40

1.00

0.50

2.00

80.00

100.00

100.00

250.00

300.00

0.04

0.25

q.s.



Item

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16



Material Name

Acetaminophen (fine powder)

Pseudoephedrine HCl

Chlorpheniramine maleate, 10% excess

Ascorbic acid

Sodium hydroxide

Edatate disodium (sodium EDTA)

Saccharin sodium

Sodium metabisulphite (sodium disulfite)

Alcohol (ethanol 95%)

Propylene glycol

Sorbitol (70% solution)

Glycerin (glycerol)

Sucrose

Quinoline yellow

Pineapple flavor

Water, purified



MANUFACTURING DIRECTIONS

1. Add 200.0 g of item 16 to the manufacturing

vessel and heat to 90˚ to 95˚C.

2. Add item 13 while mixing at slow speed. Keep

temperature at 90˚ to 95˚C.

3. Mix for 1 hour at high speed. Add items 12, 10,

and 11 to the manufacturing vessel at step above

while mixing at high speed. Mix for 10 minutes.

4. Cool the temperature to 50˚C while mixing at

slow speed.

5. Add 70.0 g of item 9 to the syrup solution while

mixing at slow speed. Load item 1 to the manufacturing vessel at step above while mixing at

high speed.

6. Mix for 30 minutes to get clear solution. Check

the clarity of the solution. Flush the solution

with nitrogen gas for 5 minutes at 1 bar.

7. Add items 6, 8, 4, and 2 to the manufacturing

vessel at step above while mixing at slow speed.

Dissolve item 3 in 2.0 g of item 16 (at 25˚C)

and check that solution is complete.

8. Add the solution to the manufacturing vessel

while mixing at slow speed.



© 2004 by CRC Press LLC



Quantity/L (g)

24.00

3.00

0.44

14.00

2.40

1.00

0.50

2.00

80.00

100.00

100.00

250.00

300.00

0.04

0.25

q.s. to 1 L



9. Dissolve item 15 in 10.0 g of item 9 in a stainless steel container and add to the manufacturing vessel while mixing at slow speed.

10. Dissolve items 5 and 7 in 20.0 g of item 16

(25˚C) and add to the manufacturing vessel at

the step above while mixing at slow speed. Dissolve item 14 in 2.0 g of item 16 (at 25˚C).

11. Transfer the color solution to the manufacturing

vessel while mixing at slow speed. Rinse the

container of color solution with 2.0 g of item

16 (25˚C), then transfer the rinsing to the manufacturing vessel and mix for 5 minutes at high

speed.

12. Make up the volume to 1.0 L with item 16, and

finally, mix for 15 to 20 minutes at high speed.

13. Check and record the pH; the limit is 5.1 to 5.2.

If required, adjust pH with 10% citric acid or

10% sodium citrate solution.

14. Assemble the filter press with 13.1 T 1000 12

sheets (K 800 14 sheets). Use changeover plate.

15. Wash the filters using about 200 L purified

water (at 25˚C) by passing water through filters

at 0.2 bar, and discard the washings.

16. Filter the syrup at 1.5 bar.

17. Recirculate about 20 to 30 mL syrup. Connect

the hose to the manufacturing vessel and transfer the filtered syrup to the storage vessel.



68



Handbook of Pharmaceutical Formulations: Liquid Products



Acyclovir Oral Suspension

Scale (mg/5 mL)

215.00

5.00

1.00

75.00

750.00

2250.00

20.00





Item

1

2

3

4

5

6

7

8



Material Name

Acyclovir

Methyl paraben

Propyl paraben

Microcrystalline cellulose (Avicel RC-591)

Glycerin (glycerol)

Sorbitol (70% solution)

Orange banana dry flavor

Water, purified



MANUFACTURING DIRECTIONS

1. Disperse item 1 in item 6. Keep stirring by

stirrer for 1 hour.

2. Heat 333.33 g of item 8 in mixer to 90˚ to 95˚C.

Dissolve items 2 and 3 while mixing. Cool to

30˚C.

3. Disperse items 4 and 5 in a stainless steel container and keep stirring for 1 hour.



Quantity/L (g)

43.00

1.00

0.20

15.00

150.00

450.00

4.00

q.s. to 1 L



4. Add step 3 into step 2 at 30˚C. Mix and homogenize for 5 minutes at high speed under vacuum

0.5 bar.

5. Add step 1 in to step 2 and mix for 5 minutes.

6. Disperse item 7 in 13.33 g of item 8. Add into

step 2.

7. Make up the volume with item 8. Finally,

homogenize for 5 minutes at high speed under

vacuum 0.5 bar.



Acyclovir Oral Suspension

Bill of Materials

Scale (mg/mL)

20.00

60.00

30.00

28.00

0.50

q.s.

q.s.



Item

1

2

3

4

5

6

7



Material Name

Acyclovir

Kollidon CL-M

Kollidon 30

Sorbitol

Citric acid

Preservative

Water, purified



MANUFACTURING DIRECTIONS

1. Suspend item 1 and item 2 in the solution of

items 3 through 7.



© 2004 by CRC Press LLC



Quantity/L (g)

20.00

60.00

30.00

28.00

0.50

q.s.

q.s. to 1 L



2. Mix vigorously to suspend.

3. Fill.



Manufacturing Formulations



69



Adapalene Solution

DIFFERIN® Solution, containing adapalene, is used for

the topical treatment of acne vulgaris. Each milliliter of

DIFFERIN® Solution contains adapalene 0.1% (1 mg) in

Bill of Materials

Scale (mg/mL)

1.00

700.00

q.s.



Item

1

2

3



Material Name

Adapalene

Polyethylene glycol 400

Alcohol



MANUFACTURING DIRECTIONS

1. Charge items 1 and 2 in a suitable mixing vessel. Stir.



© 2004 by CRC Press LLC



a vehicle consisting of polyethylene glycol 400 and SD

alcohol 40-B, 30% (w/v).



Quantity/L (g)

1.00

700.00

q.s. to 1 L



2. Add and dissolve item 1 and mix.



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