US20040166155A1 - Drug activation process and vibrational mill therefor - Google Patents
Drug activation process and vibrational mill therefor Download PDFInfo
- Publication number
- US20040166155A1 US20040166155A1 US10/481,377 US48137703A US2004166155A1 US 20040166155 A1 US20040166155 A1 US 20040166155A1 US 48137703 A US48137703 A US 48137703A US 2004166155 A1 US2004166155 A1 US 2004166155A1
- Authority
- US
- United States
- Prior art keywords
- drug
- grinding
- vibration
- activation
- frequency
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
- B02C—CRUSHING, PULVERISING, OR DISINTEGRATING IN GENERAL; MILLING GRAIN
- B02C17/00—Disintegrating by tumbling mills, i.e. mills having a container charged with the material to be disintegrated with or without special disintegrating members such as pebbles or balls
- B02C17/14—Mills in which the charge to be ground is turned over by movements of the container other than by rotating, e.g. by swinging, vibrating, tilting
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
Definitions
- This invention relates to the field of drug activation by high-energy co-grinding. It comprises a process that produces pharmaceutical composites with controlled activation and particle size. It also comprises a vibrational mill specifically adapted for the performance of this process.
- the vibrational mill is one of the types of equipment most often used for high-energy co-grinding.
- WO 9632931 discloses mechanically activated composites obtained by co-grinding of poorly soluble pharmaceutical substances and sodium starch glycolate, for example, in high energy vibration mills.
- the mill usually consists of a cylindrical chamber or reactor clad with inert material, inside which high-density grinding means are installed.
- the grinding means are bodies with a given shape, weight, volume and surface area, present inside the reactor in varying numbers but not attached to it; they are consequently free to move in response to mechanical stresses imparted outside the reactor by a vibrating mechanism.
- the grinding means are usually cylindrical bodies with flat or curved (dome-shaped) bases, made of high-density shockproof material, typically metal or metal oxide, such as aluminium oxide, zirconium oxide or steel.
- the mill To perform grinding, the mill is loaded with a preset quantity of grinding means and grinding powder, and made to vibrate. Grinding takes place by compression of the powder between the surfaces of the various grinding means which undergo free rotatory/vibratory movement.
- the vibration mechanism is produced by an electric motor fitted to the reactor, to which two eccentric counterweights are attached in such a way that they can be regulated; the stresses imparted to the reactor cause a rotary/vibratory movement of the grinding means.
- the transfer of energy from the motor to the grinding chamber therefore depends on the power of the motor and on the weights and reciprocal positions of the two counterweights, which determine the amplitude of vibration of the chamber.
- the mills are constructed so as to vary the weight and reciprocal positions of the counterweights (also called guide angles) and thus modify the amplitude of vibration; the power of the motor is fixed and constant (DM28L Food Grade Vibro-Energy Mill. Sweco Manual).
- the grinding process presents a considerable ability to activate drugs as a result of its ability to incorporate the drug into the carrier In the nanocrystalline or amorphous state (the states with the greatest solubility and bioavailability), and at the same time to reduce the size of the particles of drug/carrier composite.
- the conventional co-grinding process simultaneously leads to a reduction in the particle size of the drug/carrier composite, and at the same time to an increase in the level of activation of the drug.
- such a process can generally produce drug/carrier composites with a high level of activation and very fine particle size, but does not allow highly activated composites with a medium or coarse particle size, for example, to be produced.
- DE 4343742 describes a vibrational mill comprising an inverter which regulates the vibration frequency.
- This invention is based on the finding that if, in a co-grinding process, the vibration frequency imposed on the mill (number of oscillations in time) is modified without varying the amplitude of the vibration (extension of oscillation), the degree of activation of the drug increases in proportion to the frequency imposed, while the particle size of the end product of co-grinding (drug/carrier composite) remains substantially unchanged.
- the present invention relates to a process able to produce pharmaceutical composites with controlled activation and particle size, and a vibrational mill specifically adapted for the performance of this process.
- the subject of this invention is a process for activating a drug by co-grinding of said drug with a pharmaceutical carrier, said process being characterised in that:
- the desired degree of activation is obtained by varying the vibration frequency, while the vibration amplitude is kept constant.
- the degree of activation attained by the co-ground drug increases in proportion to the vibration frequency applied, while the particle size of the carrier-drug composite obtained remains constant.
- the frequency and keeping the amplitude constant it is now possible to control the degree of activation of the drug reliably, without affecting the particle size of the end product of co-grinding.
- drug activation means the ability to reduce or eliminate the amount of drug present in crystalline form by increasing its nanocrystalline and/or amorphous fraction.
- the working value of the amplitude of vibration is preferably between 3 mm and 15 mm of shift, most preferably between 5 mm and 12 mm, measured on the axis perpendicular to the ground. Small changes of the vibration amplitude (i.e. +/ ⁇ 10%) do not interfere with obtaining the results of the present invention.
- various drug/carrier composites with increasing degree of activation can be obtained by increasing the vibration frequency; these increases in frequency generate an increase in drug activation, while the particle size of the final drug/carrier composite remains constant.
- the vibration frequency is generated by and equal to the mill motor rotation frequency or rate.
- the working frequency is generally between 200 and 4500 rpm, preferably between 500 and 4000 rpm, most preferably between 700 and 3500 rpm; the choice of specific working value depends on the degree of activation required: the higher the frequency, the greater the degree of activation.
- the vibration amplitude can be set with known systems, for example with suitable counterweights positioned in such a way as to determine the amplitude of vibration of the grinding chamber.
- the operating frequency is set by regulating the motor rotation speed.
- the process is performed by loading the mill with a suitable amount of drug and carrier, optionally pre-mixed; preferably the drug and carrier are introduced into the mill as two separate powders.
- a suitable amount of drug and carrier optionally pre-mixed; preferably the drug and carrier are introduced into the mill as two separate powders.
- proportions of the drug and carrier of between 12:1 and 0.5:1 by weight, preferably between 5:1 and 1:1, can be used.
- the grinding time is usually between 1 and 8 hours; for each drug/carrier mixture a peak time (plateau) is present, after which grinding is complete and activation will not increase any further.
- the carrier can be any solid pharmaceutical excipient, such as cross-linked and non-cross-linked polymers; examples of these products are: cross-linked polyvinylpyrrolidone (PVP-CL), cross-linked carboxymethyl cellulose (croscarmellose), polacrilin potassium, starch and its derivatives such as sodium starch glycolate (SSG), cyclodextrin (in particular ⁇ -cyclodextrin), cellulose and its derivatives; non-polymeric carriers such as silica and alumina can also be used. To ensure a higher level of activation, cross-linked polymers are preferably used.
- PVP-CL polyvinylpyrrolidone
- croscarmellose cross-linked carboxymethyl cellulose
- polacrilin potassium starch and its derivatives
- starch and its derivatives such as sodium starch glycolate (SSG), cyclodextrin (in particular ⁇ -cyclodextrin), cellulose and its derivatives
- the present process can be performed with any solid drug.
- the process of the invention is particularly advantageous for drugs which are slightly soluble or insoluble in water, because the phenomenon of activation is observed to the greatest extent in these products.
- Drugs with particularly low solubility are defined as “class II” and “class IV” drugs according to “FDA/CDER Guidance for Industry. Waiver of in-vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a Biopharmaceutical Classification System. August 2000”.
- these products include cox-2 inhibitors, antiinflammatory drugs such as nimesulide, piroxicam, naproxene, ketoprofen, ibuprofen and diacerheine, antifungal drugs such as griseofulvin, itraconazole, fluconazole, miconazole and ketonazole, bronchodilators/anti-asthmatic drugs such as zafrilukast, salbutamol, beclomethasone, flunisolide, clenbuterol, salmeterol and budesonide, steroids such as estradiol, estriol, progesterone, megestrol acetate, medroxyprogesterone acetate, antihypertensive /antithrombotic/vasodilator drugs such as nefedipine, nicergoline, nicardipine, lisinopril, enalapril, nicorandil, celiprolol
- antiinflammatory drugs such as
- the Applicant has developed and used a new mill which includes systems designed to regulate the vibration frequency.
- This modified mill constitutes part of the present invention.
- the system which regulates the vibration frequency is generally constituted by a potentiometer (or inverter) connected to the mill motor and suitably regulable by an operator; via regulation of the motor rotation speed, the potentiometer determines the vibration frequency imposed on the chamber, and therefore the vibratory energy of the grinding means.
- the oscillation capacity of the mil remains fixed within the amplitude range originally set.
- any commonly available potentiometer can be used in the vibrational mill, provided that it is compatible with the voltage and current intensity of the mill in question.
- the potentiometer inverter
- the type of grinding means contained in the mill is not crucial to the invention, and reference should be made to the means commonly used in high-energy co-grinding as regards this aspect. They are normally bodies with a cylindrical or cylindroid shape, preferably with flat or convex bases. The dimensions of the grinding means are proportional to the volume of the mill. By way of example, means could be used in which the diameter and height are between 0.4 and 3 cm, independently of one another, and preferably between 0.6 and 1.3 cm.
- the grinding means are made of high-density shockproof material (preferably with a density greater than 3 g/cc), such as aluminium oxide, zirconium oxide or steel.
- the grinding means are introduced into the mill in the quantities normally used for this type of equipment; by way of example, the grinding means occupy 20% to 90% of the total internal volume of the grinding chamber.
- the mill forming the subject of the invention is of pharmaceutical grade, namely a mill with a steel grinding chamber and linings made of plastic materials approved for pharmaceutical and/or food uses.
- variable-frequency process enables the ideal ratio of the drug to be prepared in the amorphous, nanocrystalline or crystalline phase, without modifying the ideal particle size reduction kinetics, which could adversely affect the co-grinding process (e.g. temperature increase) and/or the subsequent processing stages (e.g. excessively fine particle size and problems of powder flow).
- the percentage of the drug in the amorphous, nanocrystalline or crystalline state was determined by differential scanning calorimetry using a Perkin-Elmer DSC7 calorimeter.
- the percentage of drug in the crystalline or nanocrystalline form is determined by comparing the fusion enthalpies relating to the crystalline form (at temperature Tm) and nanocrystalline form (at temperature T ⁇ Tm) with the enthalpy of the totally crystalline drug (100% crystallinity).
- the titre of the drug included in the carrier is determined by spectrophotometry (UV/visible spectrum) or HPLC.
- the particle size of the activated carrier/drug composite is expressed as the Specific Surface Area (SSA).
- SSA is determined by helium absorption (BET).
- the standard deviation of the percentage of amorphous, nanocrystalline and crystalline phase is 2%.
- the standard deviation of the SSA values is 0.5 m 2 /g.
- the SSA of the product remains substantially constant, regardless of the frequency values applied and the co-grinding time. Conversely, drug activation (% of amorphous and nanocrystalline phase) increases in proportion to the grinding frequency.
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Food Science & Technology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Crushing And Grinding (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/146,297 US7793871B2 (en) | 2001-06-29 | 2008-06-25 | Drug activation process and vibrational mill therefor |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IE20010620 | 2001-06-29 | ||
IE2001/0620 | 2001-06-29 | ||
PCT/EP2002/006050 WO2003002258A1 (en) | 2001-06-29 | 2002-06-03 | Drug activation process and vibrational mill therefor |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/146,297 Division US7793871B2 (en) | 2001-06-29 | 2008-06-25 | Drug activation process and vibrational mill therefor |
Publications (1)
Publication Number | Publication Date |
---|---|
US20040166155A1 true US20040166155A1 (en) | 2004-08-26 |
Family
ID=11042807
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/481,377 Abandoned US20040166155A1 (en) | 2001-06-29 | 2002-06-03 | Drug activation process and vibrational mill therefor |
US12/146,297 Expired - Fee Related US7793871B2 (en) | 2001-06-29 | 2008-06-25 | Drug activation process and vibrational mill therefor |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/146,297 Expired - Fee Related US7793871B2 (en) | 2001-06-29 | 2008-06-25 | Drug activation process and vibrational mill therefor |
Country Status (10)
Country | Link |
---|---|
US (2) | US20040166155A1 (es) |
EP (1) | EP1409140B1 (es) |
JP (1) | JP2004530557A (es) |
AT (1) | ATE301499T1 (es) |
AU (1) | AU2002304659B2 (es) |
CA (1) | CA2450900C (es) |
DE (1) | DE60205491T2 (es) |
ES (2) | ES2247336T3 (es) |
NZ (1) | NZ530825A (es) |
WO (1) | WO2003002258A1 (es) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010141063A1 (en) * | 2009-06-03 | 2010-12-09 | The Trustees Of Columbia University In The City Of New York | X-ray characterization of solid small molecule organic materials |
WO2012063246A1 (en) * | 2010-11-11 | 2012-05-18 | Mapi Pharma Ltd. | Amorphous form of lurasidone hydrochloride |
US8981095B2 (en) | 2011-07-28 | 2015-03-17 | Mapi Pharma Ltd. | Intermediate compounds and process for the preparation of lurasidone and salts thereof |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10456036B2 (en) | 2008-12-23 | 2019-10-29 | Roche Diabetes Care, Inc. | Structured tailoring |
US9117015B2 (en) | 2008-12-23 | 2015-08-25 | Roche Diagnostics Operations, Inc. | Management method and system for implementation, execution, data collection, and data analysis of a structured collection procedure which runs on a collection device |
US10437962B2 (en) | 2008-12-23 | 2019-10-08 | Roche Diabetes Care Inc | Status reporting of a structured collection procedure |
US20120011125A1 (en) | 2008-12-23 | 2012-01-12 | Roche Diagnostics Operations, Inc. | Management method and system for implementation, execution, data collection, and data analysis of a structured collection procedure which runs on a collection device |
US9918635B2 (en) | 2008-12-23 | 2018-03-20 | Roche Diabetes Care, Inc. | Systems and methods for optimizing insulin dosage |
US8849458B2 (en) | 2008-12-23 | 2014-09-30 | Roche Diagnostics Operations, Inc. | Collection device with selective display of test results, method and computer program product thereof |
KR101285520B1 (ko) | 2008-12-23 | 2013-07-17 | 에프. 호프만-라 로슈 아게 | 만성 질병을 가진 환자의 진단 또는 치료 지원을 위한 구조화된 테스팅 방법 및 그 디바이스 |
US8532933B2 (en) | 2010-06-18 | 2013-09-10 | Roche Diagnostics Operations, Inc. | Insulin optimization systems and testing methods with adjusted exit criterion accounting for system noise associated with biomarkers |
US20120173151A1 (en) | 2010-12-29 | 2012-07-05 | Roche Diagnostics Operations, Inc. | Methods of assessing diabetes treatment protocols based on protocol complexity levels and patient proficiency levels |
US8755938B2 (en) | 2011-05-13 | 2014-06-17 | Roche Diagnostics Operations, Inc. | Systems and methods for handling unacceptable values in structured collection protocols |
US8766803B2 (en) | 2011-05-13 | 2014-07-01 | Roche Diagnostics Operations, Inc. | Dynamic data collection |
WO2015071841A1 (en) | 2013-11-12 | 2015-05-21 | Druggability Technologies Holdings Limited | Complexes of dabigatran and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4076935A (en) * | 1974-12-13 | 1978-02-28 | Hoechst Aktiengesellschaft | Grinding method for cellulose |
US5275824A (en) * | 1990-03-06 | 1994-01-04 | Vectorpharma International Spa | Therapeutic compositions with controlled release of medicaments supported on crosslinked polymers and coated with polymer films, and their preparation process |
US5954565A (en) * | 1992-06-03 | 1999-09-21 | Hitachi Ltd. | Rolling mill equipped with on-line roll grinding system and grinding wheel |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3630774A (en) * | 1968-08-14 | 1971-12-28 | Corn Products Co | Disrupted granular starch products and methods of making them |
US3744726A (en) * | 1971-04-28 | 1973-07-10 | British Petroleum Co | Metal flakes |
DE2742575C2 (de) * | 1977-09-22 | 1982-05-19 | Hoechst Ag, 6000 Frankfurt | Verfahren zur Feinverteilung von Pigmenten der Dioxazinreihe |
JP2642486B2 (ja) * | 1989-08-04 | 1997-08-20 | 田辺製薬株式会社 | 難溶性薬物の超微粒子化法 |
DE4343742C2 (de) * | 1993-12-21 | 1999-10-14 | Krupp Polysius Ag | Scheibenschwingmühle |
US5612053A (en) * | 1995-04-07 | 1997-03-18 | Edward Mendell Co., Inc. | Controlled release insufflation carrier for medicaments |
WO1996032931A2 (en) * | 1995-04-20 | 1996-10-24 | Vectorpharma International S.P.A. | Composite with sodium starch glycolate as a support material and products thereof |
-
2002
- 2002-06-03 NZ NZ530825A patent/NZ530825A/en not_active IP Right Cessation
- 2002-06-03 AT AT02732748T patent/ATE301499T1/de active
- 2002-06-03 CA CA2450900A patent/CA2450900C/en not_active Expired - Fee Related
- 2002-06-03 ES ES02732748T patent/ES2247336T3/es not_active Expired - Lifetime
- 2002-06-03 WO PCT/EP2002/006050 patent/WO2003002258A1/en active IP Right Grant
- 2002-06-03 US US10/481,377 patent/US20040166155A1/en not_active Abandoned
- 2002-06-03 JP JP2003508483A patent/JP2004530557A/ja active Pending
- 2002-06-03 AU AU2002304659A patent/AU2002304659B2/en not_active Expired - Fee Related
- 2002-06-03 DE DE60205491T patent/DE60205491T2/de not_active Expired - Lifetime
- 2002-06-03 EP EP02732748A patent/EP1409140B1/en not_active Expired - Lifetime
- 2002-06-27 ES ES02754775T patent/ES2231723T3/es not_active Expired - Lifetime
-
2008
- 2008-06-25 US US12/146,297 patent/US7793871B2/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4076935A (en) * | 1974-12-13 | 1978-02-28 | Hoechst Aktiengesellschaft | Grinding method for cellulose |
US5275824A (en) * | 1990-03-06 | 1994-01-04 | Vectorpharma International Spa | Therapeutic compositions with controlled release of medicaments supported on crosslinked polymers and coated with polymer films, and their preparation process |
US5954565A (en) * | 1992-06-03 | 1999-09-21 | Hitachi Ltd. | Rolling mill equipped with on-line roll grinding system and grinding wheel |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010141063A1 (en) * | 2009-06-03 | 2010-12-09 | The Trustees Of Columbia University In The City Of New York | X-ray characterization of solid small molecule organic materials |
US20110106455A1 (en) * | 2009-06-03 | 2011-05-05 | Simon Billinge | X-ray characterization of solid small molecule organic materials |
US8751168B2 (en) | 2009-06-03 | 2014-06-10 | The Trustees Of Columbia University In The City Of New York | X-ray characterization of solid small molecule organic materials |
US8972205B2 (en) | 2009-06-03 | 2015-03-03 | The Trustees Of Columbia University In The City Of New York | X-ray characterization of solid small molecule organic materials |
WO2012063246A1 (en) * | 2010-11-11 | 2012-05-18 | Mapi Pharma Ltd. | Amorphous form of lurasidone hydrochloride |
US8981095B2 (en) | 2011-07-28 | 2015-03-17 | Mapi Pharma Ltd. | Intermediate compounds and process for the preparation of lurasidone and salts thereof |
Also Published As
Publication number | Publication date |
---|---|
WO2003002258A1 (en) | 2003-01-09 |
ATE301499T1 (de) | 2005-08-15 |
CA2450900A1 (en) | 2003-01-09 |
EP1409140A1 (en) | 2004-04-21 |
US20080251615A1 (en) | 2008-10-16 |
ES2247336T3 (es) | 2006-03-01 |
CA2450900C (en) | 2010-08-24 |
US7793871B2 (en) | 2010-09-14 |
NZ530825A (en) | 2005-03-24 |
DE60205491T2 (de) | 2006-06-01 |
AU2002304659B2 (en) | 2006-11-16 |
ES2231723T3 (es) | 2005-05-16 |
JP2004530557A (ja) | 2004-10-07 |
DE60205491D1 (de) | 2005-09-15 |
EP1409140B1 (en) | 2005-08-10 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: EURAND PHARMACEUTICALS LTD., IRELAND Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DOBETTI, LUCA;RABAGLIA, LEONARDO;BRESCIANI, MASSIMO;REEL/FRAME:015443/0521 Effective date: 20020503 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |