Platinum refractory.
\r\n\tFurther development of geophysical methods in the direction of constructing more and more adequate models of media and phenomena necessarily leads to more and more complex problems of mathematical geophysics, for which not only inverse, but also direct problems become significantly incorrect. In this regard, it is necessary to develop a new concept of regularization for simultaneously solving a system of heterogeneous operator equations.
\r\n\r\n\tCurrently, the study of processes associated not only with geophysics and astrophysics but also with biology and medicine requires even more complication of interpretation models from non-linear and heterogeneous to hierarchical. This book will be devoted to the creation of new mathematical theories for solving ill-posed problems for complicated models.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"d93195bb64405dd9e917801649f991b3",bookSignature:"Prof. Olga Alexandrovna Hachay",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8253.jpg",keywords:"Ill-Posed, Inverse Problems, Geophysics, Seismic, Electromagnetic, Thermal, Magnetic, Medicine, \r\nMathematical, Algorithms, Hierarchical, Nonlinear, Historical Description, Regularization",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 7th 2019",dateEndSecondStepPublish:"March 27th 2020",dateEndThirdStepPublish:"May 26th 2020",dateEndFourthStepPublish:"August 14th 2020",dateEndFifthStepPublish:"October 13th 2020",remainingDaysToSecondStep:"10 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"150801",title:"Prof.",name:"Olga",middleName:"Alexandrovna",surname:"Hachay",slug:"olga-hachay",fullName:"Olga Hachay",profilePictureURL:"https://mts.intechopen.com/storage/users/150801/images/system/150801.jpg",biography:"Dr. Olga A. Hachay graduated with a degree in Astrophysics from Ural State University in 1969. She obtained her PhD from the Pushkov Institute of Terrestrial Magnetism, Ionosphere and Radiowave Propagation of the Russian Academy of Sciences (IZMIRAN) in 1979 with her thesis “The inverse problem for electromagnetic research of one-dimensional medium.”\nSince 1969, she has been a scientific member of the Institute of Geophysics Ural Branch of Russian Academy of Sciences (UB RAS), Ekaterinburg, Russia. From 1995 to 2004, she served as chief of the group of seismic and electromagnetic research. Her research interests include developing new methods for searching the structure and the state of the Earth’s upper crust, as well as elaborating a new theory of interpretation of electromagnetic and seismic fields. From 2002, she has been the main scientific researcher of the Institute of geophysics UB RAS. Since 2008, she has been a lead scientific researcher for UB RAS in the laboratory of borehole geophysics. Dr. Hachay is a member of various organizations and societies, including the American Mathematical Society, Mathematical Association of America, International Association of Geomechanics, and the European Geosciences Union, among others. \nDr. Hachay is fluent in Russian, English and German language",institutionString:"Ural Branch of the Russian Academy of Sciences",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Ural Branch of the Russian Academy of Sciences",institutionURL:null,country:{name:"Russia"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"15",title:"Mathematics",slug:"mathematics"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"247865",firstName:"Jasna",lastName:"Bozic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/247865/images/7225_n.jpg",email:"jasna.b@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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[1] A common sign of relapse is a rise in the serum CA-125 level in the absence of symptoms (defined as marker-only relapse) or objective evidence of disease as assessed by physical or radiological examinations. Recurrent disease is not curable, and the majority of patients with recurrent disease will succumb to their disease irrespective of the second-line treatment modality used. As there is no compelling evidence that early treatment with chemotherapy is beneficial in relapsed asymptomatic disease, patients with marker-only-relapse are often observed. The MRC OV05/EORTC 55955 did not show a survival benefit with early treatment of relapse on the basis of a raised CA125 concentration only. [2] Some patients with asymptomatic disease with tumour-marker elevation only may develop symptomatic disease within months, while others may take years. [2] Assessment of the rate of progression by CA 125 is essential and useful for most patients with advanced ovarian cancer in remission. CA 125 is elevated in most patients with documented progressive disease. Serial measurement is a useful marker to assess the response to chemotherapy according to GCIG criteria. [3] Clinicians should keep in mind that CA 125 is not specific for ovarian cancer. Raised CA 125 levels may also be found in non-gynaecological malignancies (breast cancer and lung cancer, as well as colon and pancreatic malignancies). An elevated CA 125 can be found in patients with benign conditions such as endometriosis, pelvic inflammatory disease, and ovarian cysts.
Progressive disease — shows multiple complex cystic/solid peritoneal deposits on the liver’s surface (visceral peritoneum) and elsewhere in the peritoneal cavity.
The role of chemotherapy in the management of recurrent ovarian cancer is palliative and is usually indicated for ovarian cancer-related symptoms, or for patients with objective evidence of significant disease progression on physical or radiological examination.
The likelihood of benefit from chemotherapy treatment in patients with relapsed ovarian cancer depends on the platinum-free interval (PFI). PFI is defined as the interval between the last dose of platinum and the time of relapse. Patients with platinum-resistant disease (PFI of less than six months) are unlikely to respond to second-line platinum agents and are often managed with an alternative agent (see Table 1). Patients with platinum semi-sensitive disease (PFI of between six and 12 months) have a response rate of approximately 30% to second-line platinum treatment. In patients with fully platinum-sensitive disease (PFI more than 12 months with a subset greater than 24 months), the response rate to second-line platinum may be as high as 60–70%. [4]
The role of combination chemotherapy has been assessed in randomized trials in the setting of platinum semi-sensitive and fully sensitive relapses. Patients with fully sensitive disease should be re-challenged with a platinum-based (cisplatin or carboplatin) chemotherapy regime. [5] Patients with platinum semi-sensitive disease should be treated with a platinum-based doublet combination. It has been demonstrated that retreatment results in valuable responses that translate into improvement in quality of life and survival. Patients with a PFI of greater than six months usually receive treatment with a platinum-based regimen either as a single-agent or in combination with agents like paclitaxel [6], gemcitabine [7], or pegylated liposomal doxorubicin (PLD) [8]
\n\t\t\t\t\tAgent\n\t\t\t\t | \n\t\t\t\t\n\t\t\t\t\tAuthor\n\t\t\t\t | \n\t\t\t\t\n\t\t\t\t\tORR\n\t\t\t\t | \n\t\t\t\t\n\t\t\t\t\tPFS\n\t\t\t\t | \n\t\t\t\t\n\t\t\t\t\tOS\n\t\t\t\t | \n\t\t\t
\n\t\t\t\t\t(months)\n\t\t\t\t | \n\t\t\t\t\n\t\t\t\t\t(%)\n\t\t\t\t | \n\t\t\t\t\n\t\t\t\t\t(months)\n\t\t\t\t | \n\t\t\t\t\n\t\t\t\t\t(months)\n\t\t\t\t | \n\t\t\t\t\n\t\t\t |
Liposomal Doxorubicin | \n\t\t\tColombo [14] | \n\t\t\t15 | \n\t\t\t3.9 | \n\t\t\t13.2 | \n\t\t
Topotecan weekly | \n\t\t\tSehouli [18] | \n\t\t\t19 | \n\t\t\t3.7 | \n\t\t\t9.6 | \n\t\t
Paclitaxel weekly | \n\t\t\tMarkman [15] | \n\t\t\t20 | \n\t\t\t5.6 | \n\t\t\t13.5 | \n\t\t
Paclitaxel 3 weekly | \n\t\t\tTrimble [16] | \n\t\t\t22 | \n\t\t\t4.5 | \n\t\t\t8.8 | \n\t\t
Docetaxel | \n\t\t\tFrancis [17] | \n\t\t\t40 | \n\t\t\t5.0 | \n\t\t\t8.0 | \n\t\t
Gemcytabine | \n\t\t\tLund [19] | \n\t\t\t19 | \n\t\t\t2.8 | \n\t\t\t6.2 | \n\t\t
Pemetrexed | \n\t\t\tMiller [20] | \n\t\t\t21 | \n\t\t\t2.9 | \n\t\t\t11.4 | \n\t\t
Etoposide oral | \n\t\t\tRose [22] | \n\t\t\t26 | \n\t\t\t5.7 | \n\t\t\t10.8 | \n\t\t
Ixabepilone | \n\t\t\tDe Geest [21] | \n\t\t\t14 | \n\t\t\t4.4 | \n\t\t\t14.8 | \n\t\t
Platinum refractory.
The International Collaborative Ovarian Neoplasm-4 (ICON-4) trial compared combination chemotherapy with paclitaxel and platinum to single-agent platinum in patients with platinum-sensitive disease. In this study, most patients had a PFI of 12 months or greater. ICON-4 showed a statistically significant improvement in overall survival (OS) in favour of combination chemotherapy for recurrent ovarian cancer, with a 7% absolute increase at two years (P = 0.023). Although the ICON-4 trial showed a positive outcome, the results remain controversial because of methodological limitations. Around, 40% of patients randomized to the platinum single-agent arm never received a taxane during the course of their disease, including first-line therapy and at disease progression, raising the possibility that the sequential use of platinum followed by paclitaxel at disease progression might have conferred the same survival advantage. [6]
Docetaxel has been investigated in the treatment of metastatic ovarian cancer, in both the front-line and relapsed setting. In the front-line setting, docetaxel was shown to be equivalent to paclitaxel. [9] Docetaxel may also be a useful choice for patients at risk of developing peripheral neuropathy. [9–11]
In a subsequent study, the AGO (Arbeitsgemeinschaft Gynaekologische Onkologie) from Germany conducted a randomized Phase III trial in patients with platinum-sensitive relapse to either gemcitabine and carboplatin, or carboplatin alone. [7] PFS was 8.6 months for the combination versus 5.8 months for single-agent carboplatin (P =.0038), with no improvement in OS. Quality of life was similar between the two arms, despite a higher incidence of thrombocytopoenia, neutropoenia, and anaemia with the combination.
Rapoport et al. investigated pegylated liposomal doxorubicin (PLD) in combination with carboplatin in a Phase II trial in patients with relapsed ovarian cancer with semi-sensitive and fully sensitive relapse. Results were encouraging, with a complete response rate of 35% and a partial response rate of 32.5% (overall response, 67.5%). Median time to progression was 11.9 months, and median survival was 30.0 months. Overall responses were higher in the platinum fully sensitive subgroup as opposed to the semi-sensitive group. [12] The GCIG (Gynecologic Cancer Intergroup) conducted a Phase III study (CALYPSO trial) comparing paclitaxel and carboplatin with PLD and carboplatin in patients presenting with platinum-sensitive relapse. There was a significant improvement in median progression-free survival (PFS) (11.3 months vs. 9.4 months; P =.005), with a lower incidence of severe hypersensitivity reactions (5% vs. 18%), in favour of the PLD-containing arm. No difference in OS was noted. Toxicities were similar to the toxicities reported in the Phase II study by Rapoport et al. and included grade 2 or greater alopecia (83.6% vs. 7%) and sensory neuropathy (26.9% vs. 4.9%) in the paclitaxel-containing arm, and with more hand-foot syndrome (grades 2 to 3, 12.0% vs. 2.2%), nausea (35.2% vs. 24.2%), and mucositis (grades 2 to 3, 13.9% vs. 7%) in the PLD containing arm. [8]
As recurrent ovarian cancer is incurable, palliation and symptom control is the goal of second-line treatment. Choosing the most appropriate agent for use in the recurrent disease setting, therefore, involves balancing the need to attain a response to treatment against maintenance of reasonable quality of life. The decision to use platinum-based chemotherapy combinations or single-agent platinum in this setting should be based on a number of factors. These factors include patient age, disease burden, rate of relapse, and patient preference. For elderly patients who require chemotherapy for mild symptomatic and low tumour burden, platinum-sensitive relapse, the usage of single-agent carboplatin is a reasonable approach. PLD is a well-tolerated alternative in patients that develop an allergy to carboplatin during the course of treatment or if further use of carboplatin is contraindicated. Both agents are associated with a good quality of life as well as acceptable toxicity profiles in terms of alopecia or severe myelosuppression. A more aggressive approach is needed for younger patients with rapidly growing cancer and platinum-sensitive relapse. Combination chemotherapy with either paclitaxel and carboplatin, docetaxel and carboplatin [13], gemcitabine and carboplatin [7], or PLD and carboplatin are reasonable [8].
Patients with platinum/taxane-resistant disease (defined by a short PFI of less than six months, or progression during platinum-based chemotherapy) are best treated with agents who lack cross-resistance to platinum compounds or are not susceptible to the common resistance mechanisms.
Potentially non-cross-resistant drugs with activity in the platinum-resistant setting include PLD [14], paclitaxel [15–16], docetaxel [17], topotecan [18], gemcitabine [19], pemetrexed [20], ixabepilone [21], or oral etoposide [22] (Table 1). In the platinum-resistant setting, the overall response rate to any of these agents is approximately 20%. Responses are short, with a median PFS of four to six months. These responses are progressively shorter with each subsequent regimen.
In the setting of platinum-resistant relapse, PLD is well tolerated at doses of 40 mg/m2 given every four weeks. Common toxicities include palmer-plantar erythrodysesthesia (hand-foot syndrome) and mucositis. Topotecan may cause significant myelosuppression and fatigue. A recently reported Phase II randomized multicenter study however showed that weekly topotecan has a favourable toxicity profile compared to the conventional 5-day schedule of topotecan with similar OS. [23]
The Cochrane Gynaecological Cancer Group conducted a meta-analysis of 14 randomized trials evaluating the usefulness of PLD in relapsed epithelial ovarian cancer. Results of this meta-analysis concluded that in patients with platinum-sensitive disease, PLD and carboplatin is more effective than paclitaxel and carboplatin, and is better tolerated. Therefore, PLD and carboplatin should be considered as the first option of treatment in women with platinum-sensitive relapse. PLD alone is also a useful agent for platinum-resistant disease. It remains unclear, however, how it compares with other single agents in this subgroup, and in which order these agents should be used. There is no data available to support the use of PLD in combination with other agents in patients with platinum-resistant relapse. [24]
As a general rule, combination chemotherapy regimens are not superior to single agents in the management of patients with platinum-resistant relapse. Combination regimens are also more toxic and should not be used in this palliative setting.
Surgery for the debulking of disease at the time of relapse, referred to as secondary cytoreductive surgery, is performed in selected patients prior to second-line chemotherapy. [25]
Due to a lack of large randomized trials, conclusive data are limited regarding the benefits of secondary cytoreductive surgery. The ability to complete a successful secondary cytoreduction may identify patients presenting with a biologically less aggressive disease or those patients who have a lower tumour burden at the time of relapse. A prospective randomized trial of secondary cytoreduction is required to determine whether this procedure improves survival in these patients. The value of secondary cytoreduction is currently being investigated in two prospective, randomized trials, GOG 213 and the AGO Desktop III study.
The Gynaecologic Oncology group (GOG) currently defines \'optimal\' cytoreductive surgery as having residual tumours having a maximum diameter of 1 cm or less. Complete cytoreduction is the ideal surgical outcome in the form of microscopic disease. [26]
Secondary cytoreduction might be considered for the subgroup of patients with a progression-free interval of more than 12 to 18 months from the time of completion of adjuvant chemotherapy, localized recurrence amenable to complete cytoreduction, potentially chemosensitive disease, and good performance status. [27–31]
On the other hand, a patient with a rapid, multifocal recurrence is unlikely to obtain any clinical benefit from surgery. [26]
Pleural and peritoneal recurrence.
Palliative surgery may be indicated in patients with recurrent ovarian cancer. Standard operations performed in this setting include colostomy for relief of a large bowel obstruction, treatment of peritoneal adhesions, and management of small bowel obstruction. [32] Surgery to relieve small bowel obstruction should take into account the likelihood of continued responsiveness to chemotherapy postoperatively (platinum-sensitive as opposed to platinum-refractory disease). Women who develop a small bowel obstruction during first-line chemotherapy have aggressive and resistant ovarian cancer, and the procedure is not beneficial in this subset of patients. A palliative gastrostomy tube may be most appropriate in this situation. Best outcomes are seen in women who have had prolonged PFI, usually lasting more than one year.
Surgery is not indicated in the management of patients with a pseudo-obstruction due to an intra-abdominal carcinomatosis and infiltration of the myoenteric plexus of the small bowel. Pharmacological treatment with metoclopramide (an agent that improves motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions) may be helpful to treat this complication. A palliative colostomy may be indicated for patients developing a large bowel obstruction. This type of surgery can provide significant prolongation of survival and improved quality of life in selected patients.
Radiation therapy may be useful in the palliation of patients with recurrent ovarian cancer. Symptomatic pelvic masses may cause bleeding, pain, and rectal narrowing. Palliative pelvic radiotherapy can offer symptom relief. Cerebral or bone metastases are unusual complications of ovarian cancer and can be successfully palliated with radiotherapy.
Several investigational agents are being studied in the relapse setting.
Bevacizumab is a humanized antibody that recognizes and neutralizes vascular endothelial growth factor (VEGF). VEGF is a pro-angiogenic factor that is secreted by ovarian cancer cells. Randomized data in other metastatic malignant diseases have shown a survival advantage for the use of bevacizumab in combination with chemotherapy [33–35].
Single-agent bevacizumab has been shown by the GOG to induce a response rate of 18% in patients with relapsed ovarian cancer. In this GOG trial, there were two complete and 11 partial responses, with a median response duration of 10 months, and 25 patients (40%) survived progression-free for at least six months. Median PFS was 4.7 months and OS was 17 months. This study did not show a significant association with prior platinum sensitivity, age, number of prior chemotherapeutic regimens, or performance status. [36]
Cannistra et al. reported a risk of life-threatening bowel perforation in patients with ovarian cancer treated with bevacizumab. All patients in this trial were heavily pre-treated, with 50% having received three prior regimens. Partial responses were observed in seven patients (15.9%). Median PFS was 4.4 months (95% CI, 3.1 to 5.5 months), with a median survival duration of 10.7 months at study termination. Bevacizumab-associated grades 3 to 4 events included hypertension (9.1%), proteinuria (15.9%), bleeding (2.3%), and wound-healing complications (2.3%). The incidence of bowel perforation was 11.4%. This was higher than reported in bevacizumab trials of other tumour types. Risk factors for bevacizumab-induced bowel perforation included a higher number of prior chemotherapy regimens, radiographic presence of bowel wall involvement by tumour, or evidence of bowel obstruction. [37]
Two randomized studies (GOG-0218 and ICON7) have shown improvement in the PFS in patients with advanced ovarian cancer treated with chemotherapy and bevacizumab. [38–39] In these trials, bevacizumab was evaluated in combination with standard paclitaxel plus carboplatin as part of initial treatment for women with ovarian cancer. Both these trials met their primary endpoints and demonstrated an improvement in PFS.
In the GOG-0218 trial, 1,873 women with newly diagnosed stage III (incompletely resectable) or stage IV epithelial ovarian cancer which had undergone debulking surgery were randomized to receive one of three treatments in a double-blind, placebo-controlled trial. Each of the three study regimens comprised 22 3-week cycles of intravenous infusions on day one, with the first six cycles consisting of standard chemotherapy with carboplatin and paclitaxel. [38]
Arm 1 — Control: chemotherapy with a placebo added in cycles 2 to 22.
Arm 2 — Chemotherapy with bevacizumab (15mg per kilogram of body weight) added in cycles 2 to 6, and a placebo from cycles 7 to 22.
Arm 3 — Chemotherapy with bevacizumab added in cycles 2 to 22.
At a median follow-up of 17.4 months, the median PFS was 10.3, 11.2, and 14.1 months in the control group, the bevacizumab-initiation group, and the bevacizumab-throughout group, respectively. No significant difference in OS was reported. The potential to detect a difference in survival is likely to be limited by lack of control for multiple subsequent regimens, including crossover to bevacizumab or other anti-VEGF agents. [38]
Although bevacizumab use resulted in additional toxicity, it was not associated with a decrease in quality of life. Grade 2 or greater hypertension was significantly more frequent with use of bevacizumab than a placebo. [38]
The second trial, ICON 7 was led by the U.K. Medical Research Council Clinical Trials Unit. This trial enrolled 1528 women with histologically confirmed, high-risk, early-stage disease (FIGO stage I or IIA and clear-cell or grade 3 tumours), or advanced (FIGO stage IIB to IV) epithelial ovarian cancer, primary peritoneal cancer, or fallopian-tube cancer. Patients were randomized to receive carboplatin and paclitaxel given every three weeks for six cycles, or to the same regimen plus bevacizumab (7.5mg per kilogram) given concurrently every three weeks for five or six cycles and continued for 12 additional cycles or until disease progression. Complete or partial response rates were reported in 67% of patients in the bevacizumab group and 48% in the control group (p = 0.001). With a median follow-up of 19.4 months, the data provide clear evidence of the biologic activity of bevacizumab with a median PFS of 19 months compared to 17.4 months in the standard therapy group (HR 0.81, CI, 0.70 to 0.94; p = 004). Final survival data are expected soon. Bevacizumab treatment did not affect the delivery of chemotherapy; it was, however, associated with a significant increase in side effects, including grade 2 or greater hypertension and bowel perforation. [39]
The OCEANS (Carboplatin and Gemcitabine plus Bevacizumab in Patients with Ovary, Peritoneal, or Fallopian Tube Carcinoma) study showed a benefit for the addition of bevacizumab to platinum-based chemotherapy in terms of PFS and a trend towards a benefit in OS.
Updated data by Aghajanian et al. indicate a median PFS advantage of four months (12.4 vs. 8.4 months) (hazard ratio 0.484) and overall response rate by RECIST of 21% (response rate 78.5% vs. 57.4%) were seen when bevacizumab was added to carboplatin and gemcitabine chemotherapy. Nevertheless, no benefit in OS was seen, but the data is still immature. [40]
\n\t\t\t\t\tAgent \n\t\t\t\t | \n\t\t\t\t\n\t\t\t\t\tTarget \n\t\t\t\t | \n\t\t\t\t\n\t\t\t\t\tPhase\n\t\t\t\t | \n\t\t\t\t\n\t\t\t\t\tClinical Setting\n\t\t\t\t | \n\t\t\t
Cediranib | \n\t\t\tVEGFR1 | \n\t\t\tPhase III | \n\t\t\tConcurrent carboplatin and paclitaxel for platinum sensitive relapse | \n\t\t
VEGFR2 | \n\t\t|||
VEGFR3 | \n\t\t|||
Lymphangenesis | \n\t\t|||
C-Kit | \n\t\t|||
Aflibercept | \n\t\t\tVEGF | \n\t\t\tPhase II | \n\t\t\tIn combination with docetaxel | \n\t\t
Placental Growth Factor | \n\t\t|||
AMG 386 (Trebananib) | \n\t\t\tTIE-2 receptor | \n\t\t\tPhase III | \n\t\t\tTRINOVA-1 paclitaxel combination and maintenance in platinum sensitive and refractory relapse | \t\n\t\t
Angiopoietin-1 | \t\n\t\t|||
Angiopoietin-2 | \t\n\t\t|||
\n\t\t | |||
\n\t\t | |||
\n\t\t\t | Phase III | \n\t\t\tTRINOVA-2 PLD combination and maintenance in platinum refractory relapse | \t\n\t\t|
\n\t\t\t | Phase III | \n\t\t\tTRINOVA-3 paclitaxel and carboplatin combination and maintenance in newly diagnosed metastatic disease | \t\n\t\t|
BIBF-1120 | \n\t\t\tVEGFR | \n\t\t\tPhase II | \n\t\t\tMaintenance of relapsed ovarian cancer | \n\t\t
PDGFR | \n\t\t|||
FGFR | \n\t\t|||
Pazopanib | \n\t\t\tVEGFR-1 | \n\t\t\tPhase III | \n\t\t\tMaintenance of advanced ovarian cancer in the front-line setting | \n\t\t
VEGFR-2 | \n\t\t|||
VEGFR-3 | \n\t\t|||
PDGFR-α | \n\t\t|||
PDGFR-β | \n\t\t|||
FGFR-1 | \n\t\t|||
FGFR-3 | \n\t\t|||
C-Kit | \n\t\t|||
Olaparib | \n\t\t\tPARP | \n\t\t\tPhase III | \n\t\t\tMaintenance in inhibitor platinum-sensitive relapsed | \n\t\t
Antiangiogenesis agents under investigation for the treatment of relapsed ovarian cancer.
VEGFR: Vascular endothelial growth factor receptor
PDGFR: platelet-derived growth factor receptor
FGFR: fibroblast growth factor receptor
PARP: poly-adenosine diphosphate [ADP]-ribose polymerase
TIE-2 receptor: receptor tyrosine kinase expressed predominantly on endothelial cells
c-Kit: trans-membrane receptor tyrosine kinase KIT, which is defined by the CD117 antigen
The AURELIA randomized Phase III study showed that addition of bevacizumab to standard chemotherapy with either PLD, topotecan, or weekly paclitaxel was associated with an improvement in PFS of 3.3 months and overall response rate by RECIST of 18%. OS and quality of life data from this study are still immature. [41]
Bevacizumab is an active agent in advanced and recurrent ovarian cancer. Large clinical trials are needed to improve the knowledge of the safety and effectiveness of bevacizumab, the duration and timing of treatment, and activity of this agent when given in combination with other chemotherapeutic agents. There is also an urgent need to identify biologic predictive factors of efficacy. When to start and end anti-angiogenesis therapy remain controversial questions, and further evaluation of personalized novel angiogenesis-based therapy is needed.
Cediranib (AZD2171) is a highly potent, small-molecule, oral tyrosine kinase inhibitor of VEGFR-1, -2, and -3, and c-Kit, which compete for the ATP-binding site within the receptor kinase domain. [42–43] It is postulated that cediranib is useful in the prevention of tumour progression, by inhibiting VEGFR-2 activity and angiogenesis, and also by concomitantly inhibiting VEGFR-3 activity and lymphangiogenesis.
Cediranib has been shown to be an active drug in recurrent ovarian cancer, fallopian tube, and peritoneal cancer with the predictable toxicities observed with other tyrosine kinase inhibitors. In a Phase II trial, partial responses were seen in eight of the 46 treated patients (17.4%). [44] The original dose was 45 mg/d, but the dose was lowered to 30 mg because of toxicity observed in the first 11 patients. Major grade 3 toxicities included hypertension (46%), fatigue (24%), and diarrhoea (13%). Grade 4 toxicities included central nervous system haemorrhage (n = 1), hypertriglyceridaemia/hypercholesterolaemia/elevated lipase (n = 1), and dehydration/elevated creatinine (n = 1). No GI perforations or fistulas occurred. [44]
Initial results of the international three-arm Phase III randomized trial (ICON 6) showed that the addition of cediranib to chemotherapy (carboplatin and paclitaxel) increased PFS by about three months in women with recurrent platinum-sensitive ovarian cancer. Additional benefit was obtained when cediranib was used as maintenance therapy, increasing overall PFS over chemotherapy alone. The time to disease progression increased from 9.4 to 12.6 months and OS was extended from 17.6 to 20.3 months over a follow-up period of two years. [45, 46]
Other anti-angiogenic agents have also been evaluated in recurrent ovarian cancer.
Aflibercept is a potent inhibitor of both VEGF and placental growth factor. Aflibercept has shown anti-tumour activity in combination with docetaxel and is useful as a single agent in the reduction of malignant ascites. The combination was tested in a Phase I/II study in patients with measurable, recurrent, or persistent epithelial ovarian cancer. The confirmed objective response rate was 54% (25 of 46 patients responded to treatment, with 11 patients achieving a complete response and 14 a partial response). [47]
AMG 386 (trebananib) is a peptide-Fc fusion protein that inhibits angiogenesis by neutralizing the interaction between the Tie2 receptor and angiopoietin 1 and 2. Targeting of the angiopoietins/Tie2 pathway as a strategy to overcome bevacizumab resistance and toxicities has gained increasing interest in recent years. A randomized study of 161 patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer evaluated weekly treatment with paclitaxel plus intravenous AMG 386 at a dose of 10mg/kg week (arm A), weekly paclitaxel plus AMG 386 at a dose of 10mg/kg week (arm B), or weekly paclitaxel plus placebo (arm C). Median PFS was 7.2 months in arm A, 5.7 months in arm B, and 4.6 months in arm C. The study has shown promising anti-cancer activity with a manageable safety profile when combined with weekly paclitaxel and a dose-response effect. [48] A recent publication of 919 enrolled patients, of whom 461 were randomly assigned to the trebananib group and 458 to the placebo group, was associated with a significantly longer median progression-free survival in favour of trebananib compared to placebo (7 2 months vs. 5 4 months; hazard ratio 0.66, p<0 0001). There was no significant increase in the incidence of grade 3 or higher adverse events between treatment groups (244 [54%] of 452 patients) for the placebo group compared to 258 [56%] of 461 patients) in the trebananib group. In this Phase III study, inhibition of angiopoietins 1 and 2 with trebananib resulted in a significant prolongation in progression-free survival. The results of the ongoing TRINOVA-1, -2, and -3 trials will define the role of trebananib in the management of patients with advanced epithelial ovarian cancer. [49]
BIBF-1120 is a triple angiokinase inhibitor of VEGFR, PDGFR, and FGFR. This agent has shown promising activity in a randomized Phase II placebo-controlled trial in relapsed ovarian cancer in the maintenance setting. The study showed a 36 week PFS of 16.3% vs. 5.0% in favour of BIBF 1120 compared to the placebo group with a hazard ratio of 0.65 (95% CI, 0.42 to 1.02; P = 0.06). [50]
Pazopanib inhibits this signalling pathway via ATP-competitive inhibition of VEGFR-1, VEGFR-2, and VEGFR-3; platelet-derived growth factor receptor (PDGFR)-α, PDGFR-β; fibroblast growth factor receptor (FGFR)-1, FGFR-3, and c-Kit. [51] Friedlander et al. reported responses to pazopanib in 11 of 36 patients (31%) with advanced ovarian cancer. The median time to response was 29 days and median response duration 113 days. The overall response rate was 18% in patients with measurable disease at baseline. [52]
De Bois et al. reported results of the AGO OVAR16 trial investigating the role of pazopanib as maintenance treatment for patients with advanced ovarian cancer in the front-line setting following induction chemotherapy. A total of 940 patients with stage 3 or 4 disease were randomized. The median time from diagnosis to randomization was 7.1 months in the placebo arm and 7.0 months in the pazopanib arm. At a median follow-up of 24 months, patients in the pazopanib arm had a prolonged PFS compared to a placebo, 17.9 versus 12.3 months, respectively (HR = 0.766; 95% CI: 0.64-0.91; p = 0.0021). Sensitivity and subgroup analyses of PFS, and analysis of PFS by GCIG criteria, were consistent with the primary analysis. The first interim analysis for OS (only 189 OS events = 20.1% of the population) showed no difference between the arms. Pazopanib treatment was associated with a higher incidence of adverse and serious adverse events (26% vs. 11%). The most common toxicities included hypertension, diarrhoea, nausea, headache, fatigue, and neutropoenia. The AGO investigators concluded that pazopanib maintenance therapy provided a statistically significant and clinically meaningful PFS benefit in patients with advanced ovarian cancer. It is possible that pazopanib will be incorporated into the armamentarium of ovarian cancer drugs in routine practice in the near future. The OS data are not mature. [53–54]
A new class of agents that inhibit poly-adenosine diphosphate [ADP]-ribose polymerase (PARP) demonstrated significant activity in patients with recurrent disease, especially those with a germline mutation in BRCA1 or BRCA2. Several recent ongoing studies are evaluating the activity of PARP inhibitors in epithelial ovarian cancer, primarily in BRCA-mutation carriers. A proof-of-concept Phase I study of olaparib was conducted in 50 BRCA-carrier patients with relapsed ovarian cancer. This study showed a 40% objective response rate judged by RECIST criteria and/or a CA125 response assessed by a greater than 50% decline in CA125. Patients that were platinum sensitive had a higher chance of achieving a response to olaparib.[55] In an international multicenter Phase II study, 57 BRCA-carriers patients with recurrent ovarian cancer were enrolled in two sequential cohorts of two doses of olaparib (400 mg and 100 mg orally twice daily). The overall response rate as per the RECIST criteria was 33% in the 400 mg and 13% in the 100 mg cohort. These results suggest a possible dose-response effect. [56] Finally, PARP inhibitors may also show activity in patients with sporadic disease without germline BRCA1 or BRCA2 mutations. Gelmon et al. had shown a 24% objective response rate in relapsed ovarian cancer in the absence of BRCA1 or BRCA2 mutations to PARP inhibitors. Olaparib was well tolerated with the most common adverse events being fatigue in 70% of patients, nausea in 66%, vomiting in 39%, and decreased appetite in 36%. [57]
Ledermann et al. studied the role of olaparib maintenance in the subset of patients with relapsed platinum-sensitive high-grade serous ovarian cancer. The study was a double-blind, placebo-controlled, Phase II study. Results showed a significantly higher PFS rate compared to a placebo (median, 8.4 months vs. 4.8 months, with a hazard ratio for progression of 0.35, P < 0.001). OS analysis is not yet mature. [58]
Olaparib was also investigated in combination with chemotherapy in patients with advanced ovarian cancer. In a randomized, open-label, Phase II study, adult patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer who had received up to three previous courses of platinum-based chemotherapy and who were progression-free for at least six months before randomization received either olaparib (200 mg capsules twice daily, administered orally on days one to 10 of each 21-day cycle) plus paclitaxel (175 mg/m2, administered intravenously on day one) and carboplatin (area under the curve [AUC] 4 mg/mL per min, according to the Calvert formula, administered intravenously on day one). Subsequently, patients received either olaparib monotherapy (400 mg capsules twice daily, given continuously) until disease progression in the olaparib plus chemotherapy group, or paclitaxel (175 mg/m2 on day one) and carboplatin (AUC 6 mg/mL per min on day one) then no further treatment in the chemotherapy alone group. The progression-free survival was significantly longer in the olaparib plus chemotherapy group (median 12.2 months [95% CI 9.7–15.0]) compared to chemotherapy alone group (median 9.6 months; 95% CI 9.1–9.7 and a HR 0.51; 95% CI 0.34–0.77; p=0.0012) — the difference was more pronounced in patients with BRCA mutations (HR 0.21 [0.08–0.55]; p=0.0015). [59]
Both the U.S. Food and Drug Administration and the EMA granted accelerated approval for olaparib (Lynparza) in the treatment of women with advanced ovarian cancer associated with defective BRCA genes, as detected by an FDA-approved test. [60]
Recurrent ovarian cancer is not curable. The goals of therapy should focus on palliation of cancer-related symptoms, extension of life, and maintenance of quality of life. The outlook has clearly improved over the last decade, due to an increase in options for the management of recurrent disease. Secondary cytoreduction has been advocated, but it remains controversial. For patients with platinum-sensitive disease retreatment with a platinum or a platinum-containing combination, such as carboplatin, should be considered. For patients with platinum-refractory or platinum-resistant disease, clinical trials should be considered. For patients who are not entering a trial, treatment with agents like PLD, paclitaxel, docetaxel, topotecan, gemcitabine, pemetrexed, ixabepilone, or oral etoposide can be considered. Despite the advances made in biological and targeted therapies like bevacizumab and pazopanib in extending disease-free survival in patients with recurrent advanced ovarian cancer, further research is needed to better understand the safety and effectiveness, the optimal duration and timing of treatment, and activity in association with other chemotherapeutic agents.
Stability constant of the formation of metal complexes is used to measure interaction strength of reagents. From this process, metal ion and ligand interaction formed the two types of metal complexes; one is supramolecular complexes known as host-guest complexes [1] and the other is anion-containing complexes. In the solution it provides and calculates the required information about the concentration of metal complexes.
Solubility, light, absorption conductance, partitioning behavior, conductance, and chemical reactivity are the complex characteristics which are different from their components. It is determined by various numerical and graphical methods which calculate the equilibrium constants. This is based on or related to a quantity, and this is called the complex formation function.
During the displacement process at the time of metal complex formation, some ions disappear and form a bonding between metal ions and ligands. It may be considered due to displacement of a proton from a ligand species or ions or molecules causing a drop in the pH values of the solution [2]. Irving and Rossotti developed a technique for the calculation of stability constant, and it is called potentiometric technique.
To determine the stability constant, Bjerrum has used a very simple method, and that is metal salt solubility method. For the studies of a larger different variety of polycarboxylic acid-, oxime-, phenol-containing metal complexes, Martel and Calvin used the potentiometric technique for calculating the stability constant. Those ligands [3, 4] which are uncharged are also examined, and their stability constant calculations are determined by the limitations inherent in the ligand solubility method. The limitations of the metal salt solubility method and the result of solubility methods are compared with this. M-L, MLM, and (M3) L are some types of examples of metal-ligand bonding. One thing is common, and that is these entire types metal complexes all have one ligand.
The solubility method can only usefully be applied to studies of such complexes, and it is best applied for ML; in such types of system, only ML is formed. Jacqueline Gonzalez and his co-worker propose to explore the coordination chemistry of calcium complexes. Jacqueline and et al. followed this technique for evaluate the as partial model of the manganese-calcium cluster and spectrophotometric studies of metal complexes, i.e., they were carried calcium(II)-1,4-butanediamine in acetonitrile and calcium(II)-1,2-ethylendiamine, calcium(II)-1,3-propanediamine by them.
Spectrophotometric programming of HypSpec and received data allows the determination of the formation of solubility constants. The logarithmic values, log β110 = 5.25 for calcium(II)-1,3-propanediamine, log β110 = 4.072 for calcium(II)-1,4-butanediamine, and log β110 = 4.69 for calcium(II)-1,2-ethylendiamine, are obtained for the formation constants [5]. The structure of Cimetidine and histamine H2-receptor is a chelating agent. Syed Ahmad Tirmizi has examined Ni(II) cimetidine complex spectrophotometrically and found an absorption peak maximum of 622 nm with respect to different temperatures.
Syed Ahmad Tirmizi have been used to taken 1:2 ratio of metal and cimetidine compound for the formation of metal complex and this satisfied by molar ratio data. The data, 1.40–2.4 × 108, was calculated using the continuous variation method and stability constant at room temperature, and by using the mole ratio method, this value at 40°C was 1.24–2.4 × 108. In the formation of lead(II) metal complexes with 1-(aminomethyl) cyclohexene, Thanavelan et al. found the formation of their binary and ternary complexes. Glycine,
Using the stability constant method, these ternary complexes were found out, and using the parameters such as Δ log K and log X, these ternary complex data were compared with binary complex. The potentiometric technique at room temperature (25°C) was used in the investigation of some binary complex formations by Abdelatty Mohamed Radalla. These binary complexes are formed with 3D transition metal ions like Cu2+, Ni2+, Co2+, and Zn2+ and gallic acid’s importance as a ligand and 0.10 mol dm−3 of NaNO3. Such types of aliphatic dicarboxylic acids are very important biologically. Many acid-base characters and the nature of using metal complexes have been investigated and discussed time to time by researchers [7].
The above acids (gallic and aliphatic dicarboxylic acid) were taken to determine the acidity constants. For the purpose of determining the stability constant, binary and ternary complexes were carried in the aqueous medium using the experimental conditions as stated above. The potentiometric pH-metric titration curves are inferred for the binary complexes and ternary complexes at different ratios, and formation of ternary metal complex formation was in a stepwise manner that provided an easy way to calculate stability constants for the formation of metal complexes.
The values of Δ log K, percentage of relative stabilization (% R. S.), and log X were evaluated and discussed. Now it provides the outline about the various complex species for the formation of different solvents, and using the concentration distribution, these complexes were evaluated and discussed. The conductivity measurements have ascertained for the mode of ternary chelating complexes.
A study by Kathrina and Pekar suggests that pH plays an important role in the formation of metal complexes. When epigallocatechin gallate and gallic acid combine with copper(II) to form metal complexes, the pH changes its speculation. We have been able to determine its pH in frozen and fluid state with the help of multifrequency EPR spectroscopy [8]. With the help of this spectroscopy, it is able to detect that each polyphenol exhibits the formation of three different mononuclear species. If the pH ranges 4–8 for di- or polymeric complex of Cu(II), then it conjectures such metal complexes. It is only at alkaline pH values.
The line width in fluid solutions by molecular motion exhibits an incomplete average of the parameters of anisotropy spin Hamilton. If the complexes are different, then their rotational correlation times for this also vary. The analysis of the LyCEP anisotropy of the fluid solution spectra is performed using the parameters determined by the simulation of the rigid boundary spectra. Its result suggests that pH increases its value by affecting its molecular mass. It is a polyphenol ligand complex with copper, showing the coordination of an increasing number of its molecules or increasing participation of polyphenol dimers used as ligands in the copper coordination region.
The study by Vishenkova and his co-worker [8] provides the investigation of electrochemical properties of triphenylmethane dyes using a voltammetric method with constant-current potential sweep. Malachite green (MG) and basic fuchsin (BF) have been chosen as representatives of the triphenylmethane dyes [9]. The electrochemical behavior of MG and BF on the surface of a mercury film electrode depending on pH, the nature of background electrolyte, and scan rate of potential sweep has been investigated.
Using a voltammetric method with a constant-current potential sweep examines the electrical properties of triphenylmethane dye. In order to find out the solution of MG and BF, certain registration conditions have been prescribed for it, which have proved to be quite useful. The reduction peak for the currents of MG and BF has demonstrated that it increases linearly with respect to their concentration as 9.0 × 10−5–7.0 × 10−3 mol/dm3 for MG and 6.0 × 10−5–8.0 × 10−3 mol/dm3 for BF and correlation coefficients of these values are 0.9987 for MG and 0.9961 for BF [10].
5.0 × 10−5 and 2.0 × 10−5 mol/dm3 are the values used as the detection limit of MG and BF, respectively. Stability constants are a very useful technique whose size is huge. Due to its usefulness, it has acquired an umbrella right in the fields of chemistry, biology, and medicine. No science subject is untouched by this. Stability constants of metal complexes are widely used in the various areas like pharmaceuticals as well as biological processes, separation techniques, analytical processes, etc. In the presented chapter, we have tried to explain this in detail by focusing our attention on the applications and solutions of stability of metal complexes in solution.
Stability or formation or binding constant is the type of equilibrium constant used for the formation of metal complexes in the solution. Acutely, stability constant is applicable to measure the strength of interactions between the ligands and metal ions that are involved in complex formation in the solution [11]. A generally these 1-4 equations are expressed as the following ways:
Thus
K1, K2, K3, … Kn are the equilibrium constants and these are also called stepwise stability constants. The formation of the metal-ligand-n complex may also be expressed as equilibrium constants by the following steps:
The parameters K and β are related together, and these are expressed in the following example:
Now the numerator and denominator are multiplied together with the use of [metal-ligand] [metal-ligand2], and after the rearranging we get the following equation:
Now we expressed it as the following:
From the above relation, it is clear that the overall stability constant βn is equal to the product of the successive (i.e., stepwise) stability constants, K1, K2, K3,…Kn. This in other words means that the value of stability constants for a given complex is actually made up of a number of stepwise stability constants. The term stability is used without qualification to mean that the complex exists under a suitable condition and that it is possible to store the complex for an appreciable amount of time. The term stability is commonly used because coordination compounds are stable in one reagent but dissociate or dissolve in the presence of another regent. It is also possible that the term stability can be referred as an action of heat or light or compound. The stability of complex [13] is expressed qualitatively in terms of thermodynamic stability and kinetic stability.
In a chemical reaction, chemical equilibrium is a state in which the concentration of reactants and products does not change over time. Often this condition occurs when the speed of forward reaction becomes the same as the speed of reverse reaction. It is worth noting that the velocities of the forward and backward reaction are not zero at this stage but are equal.
If hydrogen and iodine are kept together in molecular proportions in a closed process vessel at high temperature (500°C), the following action begins:
In this activity, hydrogen iodide is formed by combining hydrogen and iodine, and the amount of hydrogen iodide increases with time. In contrast to this action, if the pure hydrogen iodide gas is heated to 500°C in the reaction, the compound is dissolved by reverse action, which causes hydrogen iodide to dissolve into hydrogen and iodine, and the ratio of these products increases over time. This is expressed in the following reaction:
For the formation of metal chelates, the thermodynamic technique provides a very significant information. Thermodynamics is a very useful technique in distinguishing between enthalpic effects and entropic effects. The bond strengths are totally effected by enthalpic effect, and this does not make any difference in the whole solution in order/disorder. Based on thermodynamics the chelate effect below can be best explained. The change of standard Gibbs free energy for equilibrium constant is response:
Where:
R = gas constant
T = absolute temperature
At 25°C,
ΔG = (− 5.708 kJ mol−1) · log β.
The enthalpy term creates free energy, i.e.,
For metal complexes, thermodynamic stability and kinetic stability are two interpretations of the stability constant in the solution. If reaction moves from reactants to products, it refers to a change in its energy as shown in the above equation. But for the reactivity, kinetic stability is responsible for this system, and this refers to ligand species [14].
Stable and unstable are thermodynamic terms, while labile and inert are kinetic terms. As a rule of thumb, those complexes which react completely within about 1 minute at 25°C are considered labile, and those complexes which take longer time than this to react are considered inert. [Ni(CN)4]2− is thermodynamically stable but kinetically inert because it rapidly exchanges ligands.
The metal complexes [Co(NH3)6]3+ and such types of other complexes are kinetically inert, but these are thermodynamically unstable. We may expect the complex to decompose in the presence of acid immediately because the complex is thermodynamically unstable. The rate is of the order of 1025 for the decomposition in acidic solution. Hence, it is thermodynamically unstable. However, nothing happens to the complex when it is kept in acidic solution for several days. While considering the stability of a complex, always the condition must be specified. Under what condition, the complex which is stable or unstable must be specified such as acidic and also basic condition, temperature, reactant, etc.
A complex may be stable with respect to a particular condition but with respect to another. In brief, a stable complex need not be inert and similarly, and an unstable complex need not be labile. It is the measure of extent of formation or transformation of complex under a given set of conditions at equilibrium [15].
Thermodynamic stability has an important role in determining the bond strength between metal ligands. Some complexes are stable, but as soon as they are introduced into aqueous solution, it is seen that these complexes have an effect on stability and fall apart. For an example, we take the [Co (SCN)4]2+ complex. The ion bond of this complex is very weak and breaks down quickly to form other compounds. But when [Fe(CN)6]3− is dissolved in water, it does not test Fe3+ by any sensitive reagent, which shows that this complex is more stable in aqueous solution. So it is indicated that thermodynamic stability deals with metal-ligand bond energy, stability constant, and other thermodynamic parameters.
This example also suggests that thermodynamic stability refers to the stability and instability of complexes. The measurement of the extent to which one type of species is converted to another species can be determined by thermodynamic stability until equilibrium is achieved. For example, tetracyanonickelate is a thermodynamically stable and kinetic labile complex. But the example of hexa-amine cobalt(III) cation is just the opposite:
Thermodynamics is used to express the difference between stability and inertia. For the stable complex, large positive free energies have been obtained from ΔG0 reaction. The ΔH0, standard enthalpy change for this reaction, is related to the equilibrium constant, βn, by the well thermodynamic equation:
For similar complexes of various ions of the same charge of a particular transition series and particular ligand, ΔS0 values would not differ substantially, and hence a change in ΔH0 value would be related to change in βn values. So the order of values of ΔH0 is also the order of the βn value.
Kinetic stability is referred to the rate of reaction between the metal ions and ligand proceeds at equilibrium or used for the formation of metal complexes. To take a decision for kinetic stability of any complexes, time is a factor which plays an important role for this. It deals between the rate of reaction and what is the mechanism of this metal complex reaction.
As we discuss above in thermodynamic stability, kinetic stability is referred for the complexes at which complex is inert or labile. The term “inert” was used by Tube for the thermally stable complex and for reactive complexes the term ‘labile’ used [16]. The naturally occurring chlorophyll is the example of polydentate ligand. This complex is extremely inert due to exchange of Mg2+ ion in the aqueous media.
The nature of central atom of metal complexes, dimension, its degree of oxidation, electronic structure of these complexes, and so many other properties of complexes are affected by the stability constant. Some of the following factors described are as follows.
In the coordination chemistry, metal complexes are formed by the interaction between metal ions and ligands. For these type of compounds, metal ions are the coordination center, and the ligand or complexing agents are oriented surrounding it. These metal ions mostly are the transition elements. For the determination of stability constant, some important characteristics of these metal complexes may be as given below.
Ligands are oriented around the central metal ions in the metal complexes. The sizes of these metal ions determine the number of ligand species that will be attached or ordinated (dative covalent) in the bond formation. If the sizes of these metal ions are increased, the stability of coordination compound defiantly decreased. Zn(II) metal ions are the central atoms in their complexes, and due to their lower size (0.74A°) as compared to Cd(II) size (0.97A°), metal ions are formed more stable.
Hence, Al3+ ion has the greatest nuclear charge, but its size is the smallest, and the ion N3− has the smallest nuclear charge, and its size is the largest [17]. Inert atoms like neon do not participate in the formation of the covalent or ionic compound, and these atoms are not included in isoelectronic series; hence, it is not easy to measure the radius of this type of atoms.
The properties of stability depend on the size of the metal ion used in the complexes and the total charge thereon. If the size of these metal ions is small and the total charge is high, then their complexes will be more stable. That is, their ratio will depend on the charge/radius. This can be demonstrated through the following reaction:
An ionic charge is the electric charge of an ion which is formed by the gain (negative charge) or loss (positive charge) of one or more electrons from an atom or group of atoms. If we talk about the stability of the coordination compounds, we find that the total charge of their central metal ions affects their stability, so when we change their charge, their stability in a range of constant can be determined by propagating of error [18]. If the charge of the central metal ion is high and the size is small, the stability of the compound is high:
In general, the most stable coordination bonds can cause smaller and highly charged rations to form more stable coordination compounds.
When an electron pair attracts a central ion toward itself, a strong stability complex is formed, and this is due to electron donation from ligand → metal ion. This donation process is increasing the bond stability of metal complexes exerted the polarizing effect on certain metal ions. Li+, Na+, Mg2+, Ca2+, Al3+, etc. are such type of metal cation which is not able to attract so strongly from a highly electronegative containing stable complexes, and these atoms are O, N, F, Au, Hg, Ag, Pd, Pt, and Pb. Such type of ligands that contains P, S, As, Br and I atom are formed stable complex because these accepts electron from M → π-bonding. Hg2+, Pb2+, Cd2+, and Bi3+ metal ions are also electronegative ions which form insoluble salts of metal sulfide which are insoluble in aqueous medium.
Volatile ligands may be lost at higher temperature. This is exemplified by the loss of water by hydrates and ammonia:
The transformation of certain coordination compounds from one to another is shown as follows:
A ligand is an ion or small molecule that binds to a metal atom (in chemistry) or to a biomolecule (in biochemistry) to form a complex, such as the iron-cyanide coordination complex Prussian blue or the iron-containing blood-protein hemoglobin. The ligands are arranged in spectrochemical series which are based on the order of their field strength. It is not possible to form the entire series by studying complexes with a single metal ion; the series has been developed by overlapping different sequences obtained from spectroscopic studies [19]. The order of common ligands according to their increasing ligand field strength is
The above spectrochemical series help us to for determination of strength of ligands. The left last ligand is as weaker ligand. These weaker ligand cannot forcible binding the 3d electron and resultant outer octahedral complexes formed. It is as-
Increasing the oxidation number the value of Δ increased.
Δ increases from top to bottom.
However, when we consider the metal ion, the following two useful trends are observed:
Δ increases with increasing oxidation number.
Δ increases down a group. For the determination of stability constant, the nature of the ligand plays an important role.
The following factors described the nature of ligands.
The size and charge are two factors that affect the production of metal complexes. The less charges and small sizes of ligands are more favorable for less stable bond formation with metal and ligand. But if this condition just opposite the product of metal and ligand will be a more stable compound. So, less nuclear charge and more size= less stable complex whereas if more nuclear charge and small in size= less stable complex. We take fluoride as an example because due to their smaller size than other halide and their highest electro negativity than the other halides formed more stable complexes. So, fluoride ion complexes are more stable than the other halides:
As compared to S2− ion, O22− ions formed more stable complexes.
It is suggested by Calvin and Wilson that the metal complexes will be more stable if the basic character or strength of ligands is higher. It means that the donating power of ligands to central metal ions is high [20].
It means that the donating power of ligands to central metal ions is high. In the case of complex formation of aliphatic diamines and aromatic diamines, the stable complex is formed by aliphatic diamines, while an unstable coordination complex is formed with aromatic diamines. So, from the above discussion, we find that the stability will be grater if the e-donation power is greater.
Thus it is clear that greater basic power of electron-donating species will form always a stable complex. NH3, CN−, and F− behaved as ligands and formed stable complexes; on the other hand, these are more basic in nature.
We know that if the concentration of coordination group is higher, these coordination compounds will exist in the water as solution. It is noted that greater coordinating tendency show the water molecules than the coordinating group which is originally present. SCN− (thiocynate) ions are present in higher concentration; with the Co2+ metal ion, it formed a blue-colored complex which is stable in state, but on dilution of water medium, a pink color is generated in place of blue, or blue color complex is destroyed by [Co(H2O)6]2+, and now if we added further SCN−, the pink color will not appear:
Now it is clear that H2O and SCN− are in competition for the formation of Co(II) metal-containing complex compound. In the case of tetra-amine cupric sulfate metal complex, ammonia acts as a donor atom or ligand. If the concentration of NH3 is lower in the reaction, copper hydroxide is formed but at higher concentration formed tetra-amine cupric sulfate as in the following reaction:
For a metal ion, chelating ligand is enhanced and affinity it and this is known as chelate effect and compared it with non-chelating and monodentate ligand or the multidentate ligand is acts as chelating agent. Ethylenediamine is a simple chelating agent (Figure 1).
Structure of ethylenediamine.
Due to the bidentate nature of ethylenediamine, it forms two bonds with metal ion or central atom. Water forms a complex with Ni(II) metal ion, but due to its monodentate nature, it is not a chelating ligand (Figures 2 and 3).
Structure of chelating configuration of ethylenediamine ligand.
Structure of chelate with three ethylenediamine ligands.
The dentate cheater of ligand provides bonding strength to the metal ion or central atom, and as the number of dentate increased, the tightness also increased. This phenomenon is known as chelating effect, whereas the formation of metal complexes with these chelating ligands is called chelation:
or
Some factors are of much importance for chelation as follows.
The sizes of the chelating ring are increased as well as the stability of metal complex decreased. According to Schwarzenbach, connecting bridges form the chelating rings. The elongated ring predominates when long bridges connect to the ligand to form a long ring. It is usually observed that an increased a chelate ring size leads to a decrease in complex stability.
He interpreted this statement. The entropy of complex will be change if the size of chelating ring is increased, i.e., second donor atom is allowed by the chelating ring. As the size of chelating ring increased, the stability should be increased with entropy effect. Four-membered ring compounds are unstable, whereas five-membered are more stable. So the chelating ring increased its size and the stability of the formed metal complexes.
The number of chelating rings also decides the stability of complexes. Non-chelating metal compounds are less stable than chelating compounds. These numbers increase the thermodynamic volume, and this is also known as an entropy term. In recent years ligands capable of occupying as many as six coordination positions on a single metal ion have been described. The studies on the formation constants of coordination compounds with these ligands have been reported. The numbers of ligand or chelating agents are affecting the stability of metal complexes so as these numbers go up and down, the stability will also vary with it.
For the Ni(II) complexes with ethylenediamine as chelating agent, its log K1 value is 7.9 and if chelating agents are trine and penten, then the log K1 values are 7.9 and 19.3, respectively. If the metal ion change Zn is used in place of Ni (II), then the values of log K1 for ethylenediamine, trine, and penten are 6.0, 12.1, and 16.2, respectively. The log βMY values of metal ions are given in Table 1.
Metal ion | log βMY (25°C, I = 0.1 M) |
---|---|
Ca2+ | 11.2 |
Cu2+ | 19.8 |
Fe3+ | 24.9 |
Metal ion vs. log βMY values.
Ni(NH3)62+ is an octahedral metal complex, and at 25 °C its log β6 value is 8.3, but Ni(ethylenediamine)32+ complex is also octahedral in geometry, with 18.4 as the value of log β6. The calculated stability value of Ni(ethylenediamine)32+ 1010 times is more stable because three rings are formed as chelating rings by ethylenediamine as compared to no such ring is formed. Ethylenediaminetetraacetate (EDTA) is a hexadentate ligand that usually formed stable metal complexes due to its chelating power.
A special effect in molecules is when the atoms occupy space. This is called steric effect. Energy is needed to bring these atoms closer to each other. These electrons run away from near atoms. There can be many ways of generating it. We know the repulsion between valence electrons as the steric effect which increases the energy of the current system [21]. Favorable or unfavorable any response is created.
For example, if the static effect is greater than that of a product in a metal complex formation process, then the static increase would favor this reaction. But if the case is opposite, the skepticism will be toward retardation.
This effect will mainly depend on the conformational states, and the minimum steric interaction theory can also be considered. The effect of secondary steric is seen on receptor binding produced by an alternative such as:
Reduced access to a critical group.
Stick barrier.
Electronic resonance substitution bond by repulsion.
Population of a conformer changes due to active shielding effect.
The macrocyclic effect is exactly like the image of the chelate effect. It means the principle of both is the same. But the macrocyclic effect suggests cyclic deformation of the ligand. Macrocyclic ligands are more tainted than chelating agents. Rather, their compounds are more stable due to their cyclically constrained constriction. It requires some entropy in the body to react with the metal ion. For example, for a tetradentate cyclic ligand, we can use heme-B which forms a metal complex using Fe+2 ions in biological systems (Figure 4).
Structure of hemoglobin is the biological complex compound which contains Fe(II) metal ion.
The n-dentate chelating agents play an important role for the formation of more stable metal complexes as compared to n-unidentate ligands. But the n-dentate macrocyclic ligand gives more stable environment in the metal complexes as compared to open-chain ligands. This change is very favorable for entropy (ΔS) and enthalpy (ΔH) change.
There are so many parameters to determination of formation constants or stability constant in solution for all types of chelating agents. These numerous parameters or techniques are refractive index, conductance, temperature, distribution coefficients, refractive index, nuclear magnetic resonance volume changes, and optical activity.
Solubility products are helpful and used for the insoluble salt that metal ions formed and complexes which are also formed by metal ions and are more soluble. The formation constant is observed in presence of donor atoms by measuring increased solubility.
To determine the solubility constant, it involves the distribution of the ligands or any complex species; metal ions are present in two immiscible solvents like water and carbon tetrachloride, benzene, etc.
In this method metal ions or ligands are present in solution and on exchanger. A solid polymers containing with positive and negative ions are ion exchange resins. These are insoluble in nature. This technique is helpful to determine the metal ions in resin phase, liquid phase, or even in radioactive metal. This method is also helpful to determine the polarizing effect of metal ions on the stability of ligands like Cu(II) and Zn(II) with amino acid complex formation.
At the equilibrium free metal and ions are present in the solution, and using the different electrometric techniques as described determines its stability constant.
This method is based upon the titration method or follows its principle. A stranded acid-base solution used as titrate and which is titrated, it may be strong base or strong acid follows as potentiometrically. The concentration of solution using 103− M does not decomposed during the reaction process, and this method is useful for protonated and nonprotonated ligands.
This is the graphic method used to determine the stability constant in producing metal complex formation by plotting a polarograph between the absences of substances and the presence of substances. During the complex formation, the presence of metal ions produced a shift in the half-wave potential in the solution.
If a complex is relatively slow to form and also decomposes at measurable rate, it is possible, in favorable situations, to determine the equilibrium constant.
This involves the study of the equilibrium constant of slow complex formation reactions. The use of tracer technique is extremely useful for determining the concentrations of dissociation products of the coordination compound.
This method is based on the study of the effect of an equilibrium concentration of some ions on the function at a definite organ of a living organism. The equilibrium concentration of the ion studied may be determined by the action of this organ in systems with complex formation.
The solution of 25 ml is adopted by preparing at the 1.0 × 10−5 M ligand or 1.0 × 10−5 M concentration and 1.0 × 10−5 M for the metal ion:
The solutions containing the metal ions were considered both at a pH sufficiently high to give almost complete complexation and at a pH value selected in order to obtain an equilibrium system of ligand and complexes.
In order to avoid modification of the spectral behavior of the ligand due to pH variations, it has been verified that the range of pH considered in all cases does not affect absorbance values. Use the collected pH values adopted for the determinations as well as selected wavelengths. The ionic strengths calculated from the composition of solutions allowed activity coefficient corrections. Absorbance values were determined at wavelengths in the range 430–700 nm, every 2 nm.
For a successive metal complex formation, use this method. If ligand is protonate and the produced complex has maximum number of donate atoms of ligands, a selective light is absorbed by this complex, while for determination of stability constant, it is just known about the composition of formed species.
Bjerrum (1941) used the method stepwise addition of the ligands to coordination sphere for the formation of complex. So, complex metal–ligand-n forms as the following steps [22]. The equilibrium constants, K1, K2, K3, … Kn are called stepwise stability constants. The formation of the complex metal-ligandn may also be expressed by the following steps and equilibrium constants.
Where:
M = central metal cation
L = monodentate ligand
N = maximum coordination number for the metal ion M for the ligand
If a complex ion is slow to reach equilibrium, it is often possible to apply the method of isotopic dilution to determine the equilibrium concentration of one or more of the species. Most often radioactive isotopes are used.
This method was extensively used by Werner and others to study metal complexes. In the case of a series of complexes of Co(III) and Pt(IV), Werner assigned the correct formulae on the basis of their molar conductance values measured in freshly prepared dilute solutions. In some cases, the conductance of the solution increased with time due to a chemical change, e.g.,
It is concluded that the information presented is very important to determine the stability constant of the ligand metal complexes. Some methods like spectrophotometric method, Bjerrum’s method, distribution method, ion exchange method, electrometric techniques, and potentiometric method have a huge contribution in quantitative analysis by easily finding the stability constants of metal complexes in aqueous solutions.
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