About us and about PVA · Preparation of Aqueous PVA Solutions Stirring the water Adding the PVA with stirring Stir continuously with or without heating Pour the water into the vessel

About us and about PVA

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JAPAN VAM & POVAL (JVP)

　Dec.1968, Shin-Etsu Vinyl Acetate Co.,Ltd and Unitika Chemical Co.,Ltd were established. 　May 2002, JAPAN VAM ＆POVAL Co.,Ltd. was

established, uniting Shin-Etsu Vinyl Acetate , Unitika Chemical, and both marketing departments. 　March 2005, JVP became a wholly-owned subsidiary of

Shin- Etsu Chemical.

Production capacities: VAM(Vinyl acetate monomer) 150,000 t/yPVA [Industrial grade] 70,000t/y

Certifications: Oct.1995: acquired ISO9002 Oct.2000: acquired ISO9001 Jan.1999: acquired ISO14001 3

JAPAN VAM & POVAL (JVP)

We have started commercial operations since 1970.

We have a lot of experience and results to produce the industrial

grade PVA. ⇒ PVA plant

Last year (2011) we built Pharmaceutical Grade PVA plant (PG-plant).

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PVA manufacturing process

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About PVA　PVA is one of the most famous water-soluble

synthetic polymers. –PVA ; the abbreviation of “polyvinyl alcohol”–Other name; PVOH, Poval

The structure of PVA

Vinyl alcohol unit Vinyl acetate unit

Hydrophilic Hydrophobic

Polymerization degree n + m Hydrolysis(mol%) n / (n + m)×100

PVA has hydrophilic groups and hydrophobic groups in the molecule. It is possible to control the viscosity, water-solubility and other properties by adjusting the polymerization degree and the hydrolysis. 6

Polymerization degree and viscosity of PVA

Tangling of molecules increases viscosity

Low polymerization degree⇒ Low viscosity(aqueous solutions)

High polymerization degree⇒ High viscosity(aqueous solutions)

Viscosity of PVA is usually expressed for a 4% aqueous solution. The viscosity range : 3 - 300 mPa･s (industrial grade)

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The relationship between hydrolysis and water solubility

Why the solubility of fully hydrolyzed PVA is low? Fully hydrolyzed PVA

Partially hydrolyzed PVA

Hydrogen Bond

- OH groups have affinity with water, but also build a powerful hydrogen bond network between PVA molecules. So it is difficult for the water molecules to enter the PVAs.

Acetyl groups loosen the hydrogen bond network and increase the water-solubility.

The hydrogen bond of PVAs affects water solubility and physical properties.

If the content of hydrogen bond increases, - water solubility is low - physical strength is high

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Hydrolysis related to other PVA properties Comparative physical properties of fully vs partially hydrolyzed PVA

Fully hydrolyzed PVA Partially hydrolyzed PVA

high lowhigh

weakStrength medium Elongation high

stable

high

Low Requires high

temperature for complete dissolution

strongStrength high Elongation low

At low temperature viscosity rises, PVA may

gellow

Viscosity Water Solubility

Water resistance Film property

Storage stability of aqueous solution

Surface activity of aqueous solution

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Next PVA’s property and target 11

PVA’s property

　Water-solubility ⇒ Non organic solvent system

　Lower viscosity of aqueous solution（than other water-soluble polymer)

⇒ Improvement of the productivity by using high concentration aqueous solution

　High tensile strength and flexibility ⇒ Preventing the crack under high humidity

　High gas barrier property(Oxygen, moisture vapor,etc) ⇒ Preventing oxidization of API, moisture protection and odor masking

　Good binding and adhesive ability ⇒ Improvement of hardness and abrasion of tablets.

It is possible to reduce the binder content.　Good emulsifying and dispersing ability⇒ It is possible to disperse the APIs which are difficult to be dissolved in the water.

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Preparation of Aqueous PVA Solutions

Stirring the water

Adding the PVA with stirring

Stir continuously with or without heating

Pour the water into the vessel and stir. [Temperature should be not more than 30℃.]

Add the PVA into the water with stirring. Stir strongly enough so that the granules do not settle on the bottom.

In the case of without heating (at 25℃), dissolving time is long [1.5-2hr] and the solution is not clear. In the case of with heating (at 50℃), dissolving time is short [0.5-1hr] and the solution is clear. ← recommended

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The viscosity of aqueous solution of various polymers.

Concentration of aqueous solution（％）

Improvement of the productivity by using high concentration aqueous solution. ⇒ for tablet coating and granulation binder

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Water-solubility of various polymers

The water solubility of PVA films is influenced by temperature of water. PVA films are easy to be dissolved at high temperature.

The water solubility of PE-05JPS is the highest of the polymers at 37℃.

⇒ for tablet coating and granulation binder

Water temperature（℃）

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PVA’s property

　Water-solubility ⇒ Non organic solvent system

　Lower viscosity of aqueous solution（than other water-soluble polymer) ⇒ Improvement of the productivity by using high concentration aqueous

solution

　Good binding and adhesive ability ⇒ Improvement of hardness and abrasion of tablets.

It is possible to reduce the binder content. 　Good emulsifying and dispersing ability ⇒ It is possible to disperse the APIs which are difficult to be

dissolved in the water. 16

　High tensile strength and flexibility ⇒ Preventing the crack under high humidity

　High gas barrier property(Oxygen, moisture vapor,etc) ⇒ Preventing oxidization of API, moisture protection and

odor masking

Tensile strength and elongation of various polymer films.

PVA films are hard and strong at low humidity , and they are flexible at high humidity.

Film Thickness ：100μm Instrument ：SHIMAZU AUTOGRAPH AGS-J Test speed ：50mm/min

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Gas barrier

Film Thickness ：100μm Temperature ：25℃ Humidity : 60%RH Instrument ：Illinos Instruments “Type-8001”

Film Thickness ：100μm Temperature ：25℃Instrument ：Systech Instruments “L80-5000”

The PVA films have high barrier performance for every gas except the water vapor. Under the general condition, PVA is good in the barrier performance for water vapor .

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PVA for tablet coatings

Oxygen barrier

Odor masking

Water vapor barrier and flexibility of film coating

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PVA’s property 　Water-solubility ⇒ Non organic solvent system

　Lower viscosity of aqueous solution（than other water-soluble polymer) ⇒ Improvement of the productivity by using high concentration aqueous solution

　Good binding and adhesive ability ⇒ Improvement of hardness and abrasion of tablets.

It is possible to reduce the binder content.　Good emulsifying and dispersing ability ⇒ It is possible to disperse the APIs which are difficult to be dissolved in the water.

　High tensile strength and flexibility ⇒ Preventing the crack under high humidity

　High gas barrier property(Oxygen, moisture vapor,etc) ⇒ Preventing oxidization of API, moisture protection and odor masking

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Target 1) Film coatings for tablets 2) Granulation binder 3) Dispersing agent for water insoluble API

Next Film coatings for tablets

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Film coating for tablets

Advantages 　 Gas barrier effect

⇒ Prevents oxidization of API, moisture protection and odor masking 　 Strength and flexibility of the film

⇒ Prevents cracks under high humidity 　 Low viscosity

⇒ Higher solid content(Improvement of productivity of coating)

Disadvantages 　 The bonding between tablets is easy to happen during coating

because PVA solution is tacky. ⇒ Spray speed is low (Productivity is not good)

Investigation of the coating formulations 22

Coating experiments(1) Formulation(uncoated tablets)

Formulation of coating fluids

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Coating experiments(2) Tested parameter of 100kg tablets

Estimation of coated tablets(1)

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Estimation of coated tablets(2) Dissolving test

Test method ： JP Dissolving test-2（Puddle method) Test fluid ： 900 mL (1)distilled water (2)simulated gastric fluid Rotation speed ： 50 rpm Sample : The coated VB2 tablets of recipe-1,-2 and HPMC (n=6) Detector ： UV 444 nm

There was no significant difference between the results from Recipe-1, Recipe-2 and HPMC.

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Estimation of coated tablets(3) Dissolving test

Storage condition (1) 40℃×75%RH (2) 50℃Storage period 3 months

Dissolving test [Test fluid: distilled water] Sample : 1) Initial 2) After 3months(40℃×75%RH) 3) After 3months(50℃)

: The coated VB2 tablets of recipe-1,-2

The dissolving speed was not influenced by long-term storage (40℃×75%RH,50℃).

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Conclusion

Combination of PVA and HPMC or PEG-6000 enabled to increase the spray speed to the practical production level. 　The drugs released immediately from the

tablets coated with Recipe-1 and Recipe-2. 　The surface of the tablets coated with

Recipe-2 were smooth and not inferior to HPMC coated tablets.

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Next Granulation binder

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Granulation in Pharmaceutical Industry

Binder ：StarchCellulose derivativePVA

PVA has good binding and adhesive ability

Improvement of hardness and abrasion of tablets ! It is possible to reduce the binder content. 30

Granulation experiment

Formulation of granules

Binder

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Granular Properties

The binding capability of PVA was better than that of HPMC and HPC, because -Granules using PVA had less ungranulated powder -Granules using PVA had less degree of compaction

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Tabletting test

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Tablet property(1) – Hardness

The tablets with PVA showed higher tablet hardness when the binder content was same. With PVA, less binder was required to obtain the same tablet hardness.

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Tablet property(2) – Friability

The tablets with PVA showed lower friability when the binder content was same. 36

Tablet property(3) – Dissolving test

There was no significant difference for the dissolution of drug between PVA, HPC and HPMC.

PVA was suitable as a granulation binder due to its higher binding capability.

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Next Pharmaceutical grade PVA “PE series” 38

Pharmaceutical PVA listed on compendial

The usable ranges of PVA are different depend on JPE, NF and EP (Not yet harmonized). Although the overwrapped spec range is narrow, we can provide various PVAs corresponding to the customers’ needs. 39

Our Pharmaceutical grade PVA

In 2012 JAPAN VAM & POVAL CO.,LTD(JVP) started manufacturing and selling the pharmaceutical grade PVA “PE series”. We have prepared the software(manufacturing control and quality control) and the hardware (buildings and facilities), compliant with the Internal- Initiative GMP standards guideline of the Japan Pharmaceutical Excipients Council (JPEC).

• Low polymerization degree • Partially hydrolyzed • fine mesh powder

• V series (powder form)V series (powder form)–High purity and low volatilization –Highly hydrolyzed grade is abundant –Bulky

•JJ--series (granular form)series (granular form)–Numerous variations available –Good handling performance

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The characteristics of PE series

1.PE series are produced by grinding, homogenizing and packaging in new facilities that are compliant with the Internal- Initiative GMP standards guidelines on hardware.

2.PE series are produced using procedures that are compliant with the Internal- Initiative GMP standards guidelines on software.

3.Certificate of Analysis issued complies with the Japanese Pharmaceutical Excipients (JPE), the United States Pharmacopeia (USP), and the European Pharmacopoeia (EP) , endorsing that the analyzed values are compliant with the requirements of each compendial. 43

Packaging of PE series

•Since FLUSH PINCH BAG is sealed by heat seal, contamination such as crape tape, sawing thread and paper dust are not observed. •Flush PINCH BAG is opened by easy-opening feature and sealed inner bag is removed and taken into hygienic environment.

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