Metal Synergy in a Potential Anti-Cancer Drug

Metal Synergy in a Potential Anti-Cancer Drug

Ruthenium teams up with platinum in a promising anticancer drug

Read more

http://www.chemistryviews.org/details/ezine/9407491/Metal_Synergy_in_a_Potential_Anti-Cancer_Drug.html?elq_mid=10181&elq_cid=1558306

/////////Ruthenium, anticancer drug, platinum

(±)-Integrifolin, Compound from plants keeps human cancer cells from multipying

CAS 89647-87-0

C₁₅ H₁₈ O_4, 262.30

Azuleno[4,​5-​b]​furan-​2(3H)​-​one, decahydro-​4,​8-​dihydroxy-​3,​6,​9-​tris(methylene)​-​, (3aR,​4R,​6aR,​8S,​9aR,​9bR)​-

• Azuleno[4,5-b]furan-2(3H)-one, decahydro-4,8-dihydroxy-3,6,9-tris(methylene)-, [3aR-(3aα,4β,6aα,8β,9aα,9bβ)]-
• (3aR,4R,6aR,8S,9aR,9bR)-Decahydro-4,8-dihydroxy-3,6,9-tris(methylene)azuleno[4,5-b]furan-2(3H)-one
• 8-epi-Deacylcynaropicrin
• 8β-Hydroxyzaluzanin C
• Integrifolin

• Integrifolin (guaianolide)

Paper

(±)-Integrifolin

Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Total Synthesis of (±)-Integrifolin

Compound from plants keeps human cancer cells from multipying

Read more at Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

http://www.chemistryviews.org/details/ezine/9412451/Total_Synthesis_of_-Integrifolin.html?elq_mid=10181&elq_cid=1558306

(±)-Integrifolin

Banksia integrifolia

Coast Banksia

Family: Proteaceae

Banksia integrifolia is a tall shrub or small tree 6 - 16m tall. It is common in sandy coastal areas, but also grows in the forests of tablelands. The light grey bark is hard and rough.

Mature leaves 5 -10 cm long, are stiff, entire (untoothed), dull dark green above and hairy-white underneath. They are generally lanceolate. Younger leaves are irregularly toothed and shorter than the mature leaves. The species name 'integrifolia' means whole-leaved.

The pale yellow flower spikes of Banksia integrifolia range from 7-14cm long and 7cm wide. The bent styles emerge from individual flowers on the spike, straightening and spreading.

A short time after flowering, the seed pods protrude cleanly from the woody cone and open to shed black, papery, winged seeds.

Banksia integrifolia flowers from January to June.

https://www.jstage.jst.go.jp/article/cpb1958/33/8/33_8_3361/_pdf

///////(±)-Integrifolin,  human cancer cells,  multipying

C=C1C(=O)O[C@@H]2[C@H]3C(=C)[C@@H](O)C[C@H]3C(=C)C[C@@H](O)[C@@H]12

Predicting the Occurrence of Sticking during Tablet Production by Shear Testing of a Pharmaceutical Powder

A larger SI indicates a greater likelihood that sticking will occur.

Defining SI for Assessing Adhesion of Powder to the Punch

One cause of sticking is that when a powder is being compacted, the adhesive force between powder particles of the tablet and the punch surface exceeds the adhesive forces of powder particles within the tablet. Φ_p represents the frictional force acting between particles in the powder bed, and Φ_w represents the frictional force between the powder and the punch surface. The larger these values, the higher the friction and adhesion of the powder. We defined SI, which represents the degree of adhesion of a powder to the punch surface, as the value obtained by dividing Φ_w by Φ_p according to the following formula.

Sticking is a failure of pharmaceutical production that occurs when a powder containing a large amount of adhesive is being tableted. This is most frequently observed when long-term tableting is carried out, making it extremely difficult to predict its occurrence during the tablet formula design stage. The efficiency of the pharmaceutical production process could be improved if it were possible to predict whether a particular formulation was likely to stick during tableting. To address this issue, in the present study we prepared tablets composed of blended ibuprofen (Ibu), a highly adhesive drug, and measured the degree of adherence of powder particles to the surface of the tablet punch. We also measured the shear stress of the powder to determine the practical angle of internal friction (Φ_p) of the powder bed as well as the angle of wall friction (Φ_w) relative to the punch surface. These values were used to define a sticking index (SI), which showed a high correlation with the amount of Ibu that adhered to the punch during tableting; sticking occurred at SI >0.3. When the amount of lubricant added to the formulation was changed to yield tablets exhibiting different SI values without changing the compounding ratio, sticking did not occur at SI ≤0.3. These results suggest that determining the SI of a pharmaceutical powder before tableting allows prediction of the likelihood of sticking during tableting.

Predicting the Occurrence of Sticking during Tablet Production by Shear Testing of a Pharmaceutical Powder

Shohei Nakamura¹⁾, Natsuki Otsuka¹⁾, Yukari Yoshino¹⁾, Takatoshi Sakamoto¹⁾, Hiroshi Yuasa¹⁾

1) Department of Pharmaceutical Technology, School of Clinical Pharmacy, College of Pharmaceutical Sciences, Matsuyama University

 Released on J-STAGE 20160501

https://www.jstage.jst.go.jp/article/cpb/64/5/64_c15-00992/_html

///////////sticking, shear stress, internal friction angle, wall friction angle, sticking index, ibuprofen,  Tablet Production, Shear Testing, Pharmaceutical Powder

3,5-Dibromo-N-(4,6-difluorobenzo[d]thiazol-2-yl)thiophene-2-carboxamide having potent anti-norovirus activity

3,5-Dibromo-N-(4,6-difluorobenzo[d]thiazol-2-yl)thiophene-2-carboxamide

New and novel anti-norovirus agents

There is an urgent need for structurally novel anti-norovirus agents. In this study, we describe the synthesis, anti-norovirus activity, and structure–activity relationship (SAR) of a series of heterocyclic carboxamide derivatives. Heterocyclic carboxamide 1 (50% effective concentration (EC₅₀)=37 µM) was identified by our screening campaign using the cytopathic effect reduction assay. Initial SAR studies suggested the importance of halogen substituents on the heterocyclic scaffold and identified 3,5-di-boromo-thiophene derivative 2j (EC₅₀=24 µM) and 4,6-di-fluoro-benzothiazole derivative 3j (EC₅₀=5.6 µM) as more potent inhibitors than 1. Moreover, their hybrid compound, 3,5-di-bromo-thiophen-4,6-di-fluoro-benzothiazole 4b, showed the most potent anti-norovirus activity with a EC₅₀ value of 0.53 µM (70-fold more potent than 1). Further investigation suggested that 4b might inhibit intracellular viral replication or the late stage of viral infection.

3,5-Dibromo-N-(4,6-difluorobenzo[d]thiazol-2-yl)thiophene-2-carboxamide (4b)

According to the same procedure used for 2f, starting from 3,5-dibromothiophene-2-carboxylic acid (286 mg, 1.00 mmol) and 4,6-difluorobenzo[d]thiazol-2-amine (204 mg, 1.10 mmol), 4b (270 mg, 60%) was obtained as white powder. mp: 245–246°C. ¹H-NMR (DMSO-d₆) δ: 7.43 (1H, dt, J=10.2, 2.0 Hz), 7.56 (1H, s), 7.83 (1H, dd, J=8.4, 2.0 Hz). ¹³C-NMR (DMSO-d₆) δ: 102.2 (dd, J=28.0, 23.1 Hz), 104.7 (dd, J=26.4, 3.3 Hz), 114.3, 118.4, 131.4 (d, J=7.4 Hz), 134.3 (d, J=10.7 Hz), 134.9, 135.2, 152.7 (d, J=241.2, 20.7 Hz), 158.3 (dd, J=242.2, 10.7 Hz), 159.0, 159.7. HPLC purity: >99%, ESI-MS m/z 453 [M+H]⁺.

Antiviral Activity and Cytotoxicity of Tetra-halogenated Hybrid Compounds

Compound	R6	R7	R8	EC50 (µM)a)	CC50 (µM)b)
4a	Cl	H	H	2.1	>100
4b	Br	H	Br	0.53	>100
4c	Cl	H	Cl	1.1	>100
4d	Cl	Cl	H	1.4	31

a) EC₅₀ was evaluated by the CPE reduction assay. 280 TCID₅₀/50 µL of MNV and a dilution series of each compound were incubated for 30 min. The mixture was exposed to RAW264.7 cells for 1 h (in duplicate). b) Cytotoxicity was evaluated by the WST-8 assay. RAW264.7 cells were treated with dilution series of each compound (in triplicate) for 72 h.

Discovery and Synthesis of Heterocyclic Carboxamide Derivatives as Potent Anti-norovirus Agents

Mai Ohba^{1) 2)}, Tomoichiro Oka³⁾, Takayuki Ando^{1) 2)}, Saori Arahata⁴⁾, Asaka Ikegaya⁴⁾, Hirotaka Takagi⁵⁾, Naohisa Ogo^{1) 2)}, Kazuhiro Owada²⁾, Fumihiko Kawamori⁴⁾, Qiuhong Wang⁶⁾, Linda J. Saif⁶⁾, Akira Asai¹⁾

1) Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka 2) Department of Pharmaceutical and Food Science, Shizuoka Institute of Environment and Hygiene 3) Department of Virology II, National Institute of Infectious Diseases 4) Department of Microbiology, Shizuoka Institute of Environment and Hygiene 5) Division of Biological Safety Control and Research, National Institute of Infectious Diseases 6) Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, College of Veterinary Medicine, The Ohio State University

Released on J-STAGE 20160501

https://www.jstage.jst.go.jp/article/cpb/64/5/64_c16-00001/_html

How to Kill Norovirus

Three Methods:Killing Norovirus with Good HygieneKilling Norovirus in Your HomeTreating NorovirusCommunity Q&A

Norovirus is a contagious virus that affects many people each year. You can get norovirus through interaction with an infected person, by eating contaminated food, touching contaminated surfaces, or drinking contaminated water. However, there are ways to kill norovirus before it infects you. To do this, you will have to maintain personal hygiene and keep your home contamination-free.

Method1

Killing Norovirus with Good Hygiene

1. 
   1
   Wash your hands thoroughly. If you think you may have come into contact with the virus, you must wash your hands thoroughly to avoid the spread of infection. To wash your hands to avoid contamination, use soap and hot water. Alcohol hand sanitizer is generally considered ineffective against this particular kind of virus. You should wash your hands if^[1]:
   

   • You have come into contact with someone who has norovirus.
   • Before and after you interact with someone with norovirus.
   • If you visit a hospital, even if you don’t think you interacted with anyone with norovirus.
   • After going to the bathroom.
   • Before and after eating.
   • If you are a nurse or doctor, wash your hands before and after coming into contact with an infected patient, even if you wear gloves.
2. 
   2
   Avoid cooking for others if you are sick. If you have been infected and are sick, do not handle any food or cook for others in your family. If you do, they are almost certain to get the infection too.
   

   • If a family member is contaminated, do not let them cook for anyone else. Try to limit the amount of time healthy family members spend with the sick family member.
3. 
   3
   Wash your food before eating or cooking it. Wash all food items such as meats, fruits and vegetables thoroughly before consumption or for use in cooking. This is important as norovirus has the tendency to survive even at temperatures well above 140 degrees Fahrenheit (60 degrees Celsius).^[2]
   

   • Remember to carefully wash any vegetables or fruit, before consuming them, whether you prefer them fresh or cooked.
4. 
   4
   Cook your food thoroughly before eating it. Seafood should be cooked thoroughly before eating it. Quick steaming your food will generally not kill the virus, as it can survive the steaming process. Instead, bake or boil your food at temperatures higher than 140F (60C) if you are concerned about it’s origins.^[3]
   

   • If you suspect any kind of food of being contaminated, you should dispose of it immediately. For instance, if a contaminated family member handled the food, you should either throw the food out or isolate it and make sure that only the person who already has the virus eats it.

Method2

Killing Norovirus in Your Home

1. 
   1
   Use bleach to clean surfaces. Chlorine bleach is an effective cleaning agent that kills norovirus. Increase the concentration or buy a new bottle of chlorine bleach if the bleach you have has been open for more than a month. Bleach becomes less effective the longer it remains open. Before applying bleach to a visible surface, test it somewhere that is not easily seen to make sure that it won’t damage the surface. If the surface is damaged by bleach, you can also use phenolic solutions, such as Pine-Sol, to clean the surface. There are certain concentrations of chlorine bleach you can use for different surfaces.^[4]
   

   • For stainless steel surfaces and items used for food consumption: Dissolve one tablespoon of bleach in a gallon of water and clean the stainless steel.
   • For non-porous surfaces like countertops, sinks, or tile floors: Dissolve one third of a cup of bleach in a gallon of water.
   • For porous surfaces, like wooden floors: Dissolve one and two thirds of a cup of bleach in a gallon of water.
2. 
   2
   Rinse surfaces with clean water after using bleach. After cleaning the surfaces, leave the solution to work for 10 to 20 minutes. After the time period elapses, rinse the surface with clean water. After these two steps, close off the area, and leave it like that for one hour.
   

   • Leave the windows open, if possible, as breathing in bleach can be hazardous to your health.
3. 
   3
   Clean areas exposed to feces or vomit. For areas exposed to feces or vomit contamination there are special cleaning procedures that you should try to follow. This is because the vomit or feces of a person contaminated with norovirus can easily cause you to become infected. To clean the vomit or feces:
   

   • Put disposable gloves on. Consider wearing a facemask that covers your mouth and nose as well.
   • Using paper towels, gently clean the vomit and feces. Be careful not to splash or drip while cleaning.
   • Use disposable cloths to clean and disinfect the entire area with chlorine bleach.
   • Use sealed plastic bags to dispose of all the waste materials.
4. 
   4
   Clean your carpets. If the feces or vomit gets on a carpeted area, there are other steps you can take to make sure that the area is clean and disinfected. To clean the carpeted area:
   

   • Wear disposable gloves if you can while cleaning the carpets. You should also consider wearing a facemask that covers your mouth and nose.
   • Use any absorbent material to clean all the visible feces or vomit. Place all contaminated materials in a plastic bag to prevent aerosols from forming. The bag should be sealed and put into the garbage can.
   • The carpet should then be cleaned with steam at 170 degrees Fahrenheit (76 degrees Celsius) for about five minutes, or, if you want to save time, clean the carpet for one minute with 212 degrees Fahrenheit (100 degrees Celsius) steam.
5. 
   5
   Disinfect clothing. If any of your clothing or a family member’s clothing has become contaminated, or is suspected of having been contaminated, you should take care when washing the fabric. To clean clothing and linens:
   

   • Remove any traces of vomit or feces by wiping it away with paper towels or a disposable absorbent material.
   • Put the contaminated clothing into the washing machine in a pre-wash cycle. After this stage is complete, wash the clothes using a regular washing cycle and detergent. The clothes should be dried separately from the uncontaminated clothes. A drying temperature exceeding 170 degrees Fahrenheit is recommended.
   • Do not wash contaminated clothing with uncontaminated cleaning.

Method3

Treating Norovirus

1. 
   1
   Recognize symptoms. If you think you may have been infected with norovirus, it is helpful to know what symptoms to look for. If you do have the virus, the following steps will help you to deal with the illness while it lasts. Symptoms include^[5]:
   

   • Fever. Just like in any other infection, the norovirus infection will cause fever. Fever is a way in which the body fights infection. The body temperature will rise, making the virus more vulnerable to the immune system. Your body temperature will most likely rise above 100.4 degrees Fahrenheit (38 degrees Celsius) when suffering from a Norovirus infection.
   • Headaches. High body temperatures will cause blood vessels to dilate in your entire body, including your head. The high amount of blood inside your head will cause pressure to build up, and the protective membranes covering your brain will suffer inflammation and become painful.
   • Stomach cramps. Norovirus infections usually settle in the stomach. Your stomach may become inflamed, causing pain.
   • Diarrhea. Diarrhea is a common symptom of Norovirus contamination. It occurs as a defense mechanism, through which the body is trying to flush out the virus.
   • Vomiting. Vomiting is another common symptom of an infection with Norovirus. Like in the case of diarrhea, the body is trying to eliminate the virus from the system by vomiting.
2. 
   2
   Understand that while there is no treatment, there are ways to manage symptoms. Unfortunately, there is no specific drug that acts against the virus. However, you can combat the symptoms that the norovirus causes. Remember that the virus is self-limiting, which means that it generally goes away on its own.
   

   • The virus generally lasts for a few days to a week.
3. 
   3
   Drink lots of fluids. Consuming a lot of water and other fluids will help to keep you hydrated. This can help to keep your fever low and your headaches to a minimum. It is also important to drink water if you have been vomiting or have had diarrhea. When these too symptoms occur, it is very likely that you will become dehydrated.
   

   • If you get bored with water, you can drink ginger tea, which may help to manage your stomach pains while also hydrating you.
4. 
   4
   Consider taking anti-vomiting drugs. Anti-emetic (vomit-preventing) drugs such as ondansetron and domperidone can be given to provide symptomatic relief if you are vomiting frequently.^[6]
   

   • However, keep in mind that these drugs can only be obtained with a prescription from your doctor.
5. 
   5
   Seek medical help if the infection is severe. As mentioned above, most infections subside after a few days. If the virus persists for longer than a week, you should consider seeking medical help. This is particularly important if the person who is sick is a child or elderly person, or a person with lowered immunity

////////////norovirus, heterocyclic carboxamide, antiviral activity, murine norovirus

Brc1cc(Br)sc1C(=O)Nc2nc3c(F)cc(F)cc3s2

Preparation and Evaluation of Solid Dispersion Tablets by a Simple and Manufacturable Wet Granulation Method Using Porous Calcium Silicate

The aim of this study was to prepare and evaluate solid dispersion tablets containing a poorly water-soluble drug using porous calcium silicate (PCS) by a wet granulation method. Nifedipine (NIF) was used as the model poorly water-soluble drug. Solid dispersion tablets were prepared with the wet granulation method using ethanol and water by a high-speed mixer granulator. The binder and disintegrant were selected from 7 and 4 candidates, respectively. The dissolution test was conducted using the JP 16 paddle method. The oral absorption of NIF was studied in fasted rats. Xylitol and crospovidone were selected as the binder and disintegrant, respectively. The dissolution rates of NIF from solid dispersion formulations were markedly enhanced compared with NIF powder and physical mixtures. Powder X-ray diffraction (PXRD) confirmed the reduced crystallinity of NIF in the solid dispersion formulations. Fourier transform infrared (FT-IR) showed the physical interaction between NIF and PCS in the solid dispersion formulations. NIF is present in an amorphous state in granules prepared by the wet granulation method using water. The area under the plasma concentration–time curve (AUC) and peak concentration (C_max) values of NIF after dosing rats with the solid dispersion granules were significantly greater than those after dosing with NIF powder. The solid dispersion formulations of NIF prepared with PCS using the wet granulation method exhibited accelerated dissolution rates and superior oral bioavailability. This method is very simple, and may be applicable to the development of other poorly water-soluble drugs.

https://www.jstage.jst.go.jp/article/cpb/64/4/64_c15-00838/_article

 

The ‘Biopharmaceutics Classification System’ (BCS) is a very important key word in the research and development of oral formulations. The BCS classifies drugs into four classes depending on the solubility and membrane permeability of the drug. Most oral formulations show drug efficacy by first dissolving in the digestive tract then being absorbed through the membrane of the small intestine, thus entering the circulation. Oral formulations have been developed using various strategies depending on the drug’s BCS class, solubility, and membrane permeability. It was recently estimated that between 40 and 70% of all new chemical entities identified in drug discovery programs are insufficiently soluble in aqueous media.......... read all

Conclusion

Solid dispersion formulations of NIF with PCS using the wet granulation method were prepared and evaluated. These formulations exhibited much higher dissolution rates than NIF powder, comparable to ASD. Furthermore, these formulations provided superior bioavailability in rats compared with NIF powder. NIF was present in the amorphous state in the granules after preparation by a wet granulation method using water. The wet granulation method proposed here is very simple, and may be applicable to other poorly water-soluble drugs.

Preparation and Evaluation of Solid Dispersion Tablets by a Simple and Manufacturable Wet Granulation Method Using Porous Calcium Silicate

Yumi Fujimoto¹⁾, Nobuaki Hirai¹⁾, Tomoka Takatani-Nakase¹⁾, Koichi Takahashi¹⁾

1) Department of Pharmaceutics, School of Pharmaceutical Sciences, Mukogawa Women’s University

 Released on J-STAGE 20160401

https://www.jstage.jst.go.jp/article/cpb/64/4/64_c15-00838/_article

 

The ‘Biopharmaceutics Classification System’ (BCS) is a very important key word in the research and development of oral formulations. The BCS classifies drugs into four classes depending on the solubility and membrane permeability of the drug. Most oral formulations show drug efficacy by first dissolving in the digestive tract then being absorbed through the membrane of the small intestine, thus entering the circulation. Oral formulations have been developed using various strategies depending on the drug’s BCS class, solubility, and membrane permeability. It was recently estimated that between 40 and 70% of all new chemical entities identified in drug discovery programs are insufficiently soluble in aqueous media.......... read all

Conclusion

Solid dispersion formulations of NIF with PCS using the wet granulation method were prepared and evaluated. These formulations exhibited much higher dissolution rates than NIF powder, comparable to ASD. Furthermore, these formulations provided superior bioavailability in rats compared with NIF powder. NIF was present in the amorphous state in the granules after preparation by a wet granulation method using water. The wet granulation method proposed here is very simple, and may be applicable to other poorly water-soluble drugs.

//////////////// poorly water-soluble drug, porous calcium silicate (PCS), wet granulation method, dissolution, surface solid dispersion, high-speed mixer granulator,

A Novel Scale Up Model for Prediction of Pharmaceutical Film Coating Process Parameters

In the pharmaceutical tablet film coating process, we clarified that a difference in exhaust air relative humidity can be used to detect differences in process parameters values, the relative humidity of exhaust air was different under different atmospheric air humidity conditions even though all setting values of the manufacturing process parameters were the same, and the water content of tablets was correlated with the exhaust air relative humidity. Based on this experimental data, the exhaust air relative humidity index (EHI), which is an empirical equation that includes as functional parameters the pan coater type, heated air flow rate, spray rate of coating suspension, saturated water vapor pressure at heated air temperature, and partial water vapor pressure at atmospheric air pressure, was developed. The predictive values of exhaust relative humidity using EHI were in good correlation with the experimental data (correlation coefficient of 0.966) in all datasets. EHI was verified using the date of seven different drug products of different manufacturing scales. The EHI model will support formulation researchers by enabling them to set film coating process parameters when the batch size or pan coater type changes, and without the time and expense of further extensive testing.

EHI is defined as the following equation:

In general, pharmaceutical film coatings are applied in order to protect core tablets from light or for masking the taste of the active pharmaceutical ingredients. Therefore, the surface state of the coating layer is important to maintain the expected performance. During the coating process, however, the coating layer surface state is affected by the water content of the tablets. In a conventional approach, the water content of drug products is maintained at the validated level by monitoring the product’s temperature and/or the exhaust air temperature during the coating process. In a scale up study, the batch scale and manufacturing equipment are changed according to the progress of the process development stage. At each stage, the water content of drug products is constantly monitored and well-controlled to secure the consistency of the drug product’s quality. In this approach, numerous experiments are necessary to optimize the process parameters in each batch scale. As a result, the costs of materials, human resources, and time for development will become considerable.

A Novel Scale Up Model for Prediction of Pharmaceutical Film Coating Process Parameters

Yasuhiro Suzuki1), Tatsuya Suzuki1), Hidemi Minami1), Katsuhide Terada2)

1) Formulation Technology Research Laboratories, Daiichi Sankyo Co., Ltd. 2) Faculty of Pharmaceutical Science, Toho University

Released on J-STAGE 20160301

https://www.jstage.jst.go.jp/article/cpb/64/3/64_c15-00644/_article

Chemical and Pharmaceutical Bulletin
Vol. 64 (2016) No. 3 p. 215-221

http://doi.org/10.1248/cpb.c15-00644

Conclusion

In this study, the relationship between film coating process parameters and EARH was clarified. In addition, it was confirmed that the EARH affected the water content of tablets. These results indicated that the water content of tablets can be regulated by controlling the EARH. From these results, we proposed the EHI for quantification of the pharmaceutical film coating process. The fitting parameters in the EHI equation were set using the experimental data of 10 drug products and 7 kinds of pan coaters. These fitting parameters of EHI were validated by evaluating the correlation coefficient determined by comparing the calculated values of EARH and the measured experimental values of EARH from various drug products, pan coater scales and coating parameters. The main advantage of the EHI method is that commercial scale coating conditions can be predicted using only one film coating experimental result from a lab-scale pan coater.

/////////pan coater, exhaust air relative humidity index (EHI), scale up, drying ability, atmospheric air, tablet water content

Preparation of Fine Particles with Improved Solubility Using a Complex Fluidized-Bed Granulator Equipped with a Particle-Sizing Mechanism

Fig. 1. Schematic Representation of a Complex Fluidized-Bed Granulator

1: Exhaust air, 2: bag filter, 3: partition tube, 4: impeller, 5: rotor disc, 6: inlet air, 7: screen, 8: spray nozzle.

Preparation of Fine Particles with Improved Solubility Using a Complex Fluidized-Bed Granulator Equipped with a Particle-Sizing Mechanism

Shouichi Hosaka¹⁾, Yasufumi Okamura¹⁾, Yuji Tokunaga¹⁾

1) Research and Development Division, Sawai Pharmaceutical Co., Ltd.

Released on J-STAGE 20160601

Chemical and Pharmaceutical Bulletin
Vol. 64 (2016) No. 6 p. 644-649

http://doi.org/10.1248/cpb.c15-00640

https://www.jstage.jst.go.jp/article/cpb/64/6/64_c15-00640/_html

 

Abstract

A new type of fluidized-bed granulator equipped with a particle-sizing mechanism was used for the preparation of fine particles that improved the solubility of a poorly water-soluble drug substance. Cefteram pivoxyl (CEF) was selected as a model drug substance, and its solution with a hydrophilic polymer, hydroxypropyl cellulose (HPC-L), was sprayed on granulation grade lactose monohydrate (Lac). Three types of treated particles were prepared under different conditions focused on the spraying air pressure and the amount of HPC-L. When the amount of HPC-L was changed, the size of the obtained particles was similar. However, particle size distribution was dependent on the amount of HPC-L. Its distribution became more homogenous with greater amounts of HPC-L, but the particle size distribution obtained by decreasing the spraying air pressure was not acceptable. By processing CEF with HPC-L using a complex fluidized-bed granulator equipped with a particle-sizing mechanism, the dissolution ratio was elevated by approximately 40% compared to that of unprocessed CEF. Moreover, in the dissolution profile of treated CEF, the initial burst was suppressed, and nearly zero order release was observed up to approximately 60% in the dissolution profile. This technique may represent a method with which to design fine particles of approximately 100 µm in size with a narrow distribution, which can improve the solubility of a drug substance with low solubility.

Conclusion

Three types of treated particles were prepared using a complex fluidized-bed granulator equipped with a particle-sizing mechanism under different conditions focused on the spraying air pressure and the amount of HPC-L. When the amount of HPC-L was changed, the size of the obtained particles was similar. However, particle size distribution was dependent on the amount of HPC-L. Its distribution became more homogenous with greater amounts of HPC-L, but the particle size distribution obtained by decreasing the spraying air pressure was not acceptable.

By processing CEF with HPC-L using this device, the dissolution ratio was elevated by approximately 40% compared to that of unprocessed one. Moreover, in the dissolution profile of treated CEF, the initial burst was suppressed, and nearly zero order release was observed up to approximately 60% in the dissolution profile.

The present method is applicable to the design of fine particles of approximately 100 µm in size with a narrow distribution, which improved the solubility of drug substance.

////////fine particle, particle size distribution, dissolution, complex fluidized-bed granulator